Autolus Therapeutics plc (AUTL) 2024年年度報告「NASDAQ」.pdf

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1、Table of contentsUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549FORM 10-K ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2024OR TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE AC

2、T OF 1934for the transition period from toCommission file number:001-38547Autolus Therapeutics plc(Exact name of Registrant as specified in its charter)England and WalesNot applicable(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identification No.)The Mediaworks191 Wo

3、od Lane,London,W12 7FPUnited Kingdom(44)20 3829 6230(Address of principal executive offices)(Registrants telephone number,including area code)Securities registered pursuant to Section 12(b)of the Act:Title of each classTrading Symbol(s)Name of each exchange on which registeredAmerican Depositary Sha

4、res,each representing one ordinary share,nominal value of$0.000042 per shareAUTLThe Nasdaq Global Select MarketOrdinary shares,nominal value$0.000042 per share*The Nasdaq Stock Market LLC*Not for trading,but only in connection with the listing of the American Depositary Shares on The Nasdaq Stock Ma

5、rket LLC.Securities registered or to be registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to

6、 Section 13 or 15(d)of the Securities Exchange Act of 1934.Yes No 1Table of contentsIndicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for suchshorter period that th

7、e registrant was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.40

8、5 of this chapter)during the preceding 12 months(or for such shorter period that the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging

9、 growth company.See the definitionsof“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filerAccelerated filerNon-accelerated filerSmaller reporting companyEmerging growth companyIf an emerging gro

10、wth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standardsprovided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and

11、 attestation to its managements assessment of the effectiveness of its internal control over financial reporting under Section404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that prepared or issued its audit report.If securities are registered pursuant to Sec

12、tion 12(b)of the Act,indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error topreviously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery an

13、alysis of incentive-based compensation received by any of the registrants executive officersduring the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No As of June 30,2024,the aggregate marke

14、t value of voting and non-voting common equity held by non-affiliates of the registrant was approximately$613,667,644 based on the closing sale price onthat date of$3.48 per ADS.Shares held by each executive officer and director and by each other person who may be deemed to be an affiliate of the Re

15、gistrant have been excluded from thiscomputation.The determination of affiliate status for this purpose is not necessarily a conclusive determination for other purposes.As of March 19,2025,there were 266,128,900 of the registrants ordinary shares(including in the form of ADSs),with a nominal value o

16、f$0.000042 per share,outstanding.2Table of contentsEXPLANATORY NOTEAutolus Therapeutics plc(the“Company”),a corporation organized under the laws of England and Wales,qualifies as a“foreign private issuer,”as defined in Rule 3b-4 under the SecuritiesExchange Act of 1934(the“Exchange Act”)in the Unite

17、d States.The Company has voluntarily elected to file annual reports on Form 10-K,quarterly reports on Form 10-Q and current reports onForm 8-K with the United States Securities and Exchange Commission(the“SEC”)instead of filing on the reporting forms available to foreign private issuers.Although the

18、 Company has voluntarily chosen to file periodic reports,current reports and registration statements on U.S.domestic issuer forms,the Company intends to maintain its status asa foreign private issuer.Accordingly,as a foreign private issuer,the Company remains exempt from the U.S.federal proxy rules

19、pursuant to Section 14 of the Exchange Act and Regulations 14A and14C thereunder,Regulation FD,and its officers,directors,and principal shareholders are not subject to the reporting and short-swing profit recovery provisions contained in Section 16 of theExchange Act.TABLE OF CONTENTSPagePART I7Item

20、 1.Business7Item 1A.Risk Factors46Item 1B.Unresolved Staff Comments97Item 1C.Cybersecurity98Item 2.Properties99Item 3.Legal Proceedings99Item 4.Mine Safety Disclosures99PART II100Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities100Item

21、6.Reserved101Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations101Item 7A.Quantitative and Qualitative Disclosures About Market Risk115Item 8.Financial Statements and Supplementary Data116Item 9.Changes in and Disagreements With Accountants on Accounting and

22、Financial Disclosures117Item 9A.Controls and Procedures117Item 9B.Other Information118Item 9C.Disclosure Regarding Foreign Jurisdiction that Prevent Inspections118PART III119Item 10.Directors,Executive Officers and Corporate Governance119Item 11.Executive Compensation127Item 12.Security Ownership of

23、 Certain Beneficial Owner and Management and Related Stockholder Matters134Item 13.Certain Relationships and Related Transactions,and Director Independence136Item 14.Principal Accounting Fees and Services139PART IV140Item 15.Exhibits,Financial Statement Schedules140Item 16.Form 10-K Summary142Signat

24、ures1423Table of contentsGENERAL INFORMATIONAll references in this Annual Report on Form 10-K(the“Annual Report”)to“Autolus,”the“Group,”the“company,”“we,”“us”and“our”refer to Autolus Therapeutics plc and itsconsolidated subsidiaries,except where the context otherwise requires.Autolus,AUCATZYL and ou

25、r other trademarks or service marks appearing in this Annual Report are our property.Solely for convenience,the trademarks and trade names in this AnnualReport we referred to without the and symbols,but such references should not be construed as any indicator that their respective owners will not as

26、sert,to the fullest extent under applicable law,their rights thereto.Products or service names of other companies mentioned in this Annual Report may be trademarks,trade names or service marks of their respective owners.SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTSThis Annual Report on Form 10-K

27、 contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933,as amended(the“Securities Act”),and Section 21Eof the Exchange Act,that relate to future events or to our future operations or financial performance.Any forward-looking statement involves known and u

28、nknown risks,uncertainties and otherfactors that may cause our actual results,levels of activity,performance or achievements to differ materially from any future results,levels of activity,performance or achievements expressed orimplied by such forward-looking statement.In some cases,forward-looking

29、 statements are identified by the words“anticipate,”“believe,”“continue,”“could,”“estimate,”“expect,”“future,”“goals,”“intend,”“likely,”“may,”“might,”“ongoing,”“objective,”“plan,”“potential,”“predict,”“project,”“seek,”“should,”“strategy,”“target,”“will”and“would”or the negative of these terms,or oth

30、er comparable terminology intended to identify statements about the future,although not all forward-looking statements contain these identifying words.These statements involve known andunknown risks,uncertainties and other important factors that may cause our actual results,levels of activity,perfor

31、mance or achievements to be materially different from the information expressed orimplied by these forward-looking statements.The forward-looking statements contained in this Annual Report on Form 10-K are based upon information available to us as of the date of this AnnualReport and,while we believ

32、e we have a reasonable basis for each forward-looking statement contained in this Annual Report,we caution you that these statements are based on a combination of factsand factors currently known by us and our expectations of the future,about which we cannot be certain.Forward-looking statements inc

33、lude statements about:the therapeutic potential and expected clinical benefits of AUCATZYL/obe-cel(obecabtagene autoleucel)for adult patients with relapsed or refractory B-cell precursor acute lymphoblasticleukemia(“r/r B-ALL”);our ability to generate revenues from AUCATZYL,which is dependent upon m

34、aintaining significant market acceptance among physicians,patients and healthcare payors;our ability to maintain regulatory approval of AUCATZYL in the United States(“US”),to obtain and maintain regulatory approval for obe-cel for adult r/r B-ALL in additional territoriesand the timing thereof,and t

35、o obtain and maintain regulatory approval of our other product candidates in the indications for which we plan to develop them,and any related restrictions,limitations or warnings in the label of an approved drug or therapy;our expectations regarding the commercialization and marketing of AUCATZYL f

36、or adult r/r B-ALL,including expanding into additional territories and the related timing of reachingpatients in such territories;the development of our commercial product and product candidates,including statements regarding the initiation,timing,progress and the results of clinical studies or tria

37、ls and relatedpreparatory work,the period during which the results of the trials will become available and our research and development programs;our estimates regarding expenses,future revenue,capital requirements and needs for additional financing;our commercialization,marketing and manufacturing c

38、apabilities and strategy for AUCATZYL,including our ability to successfully recruit and retain sales and marketing personnel and tosuccessfully build the market for AUCATZYL;our expectations about the willingness of healthcare providers to recommend AUCATZYL to people with adult r/r B-ALL;the impact

39、s of public health crises and their effects on our operations and business,including interruption of key clinical trial activities,such as clinical trial site monitoring,access tocapital,and potential disruption in the operations and business of third-party manufacturers,clinical sites,contract rese

40、arch organizations(“CROs”),other service providers andcollaborators with whom we conduct business;our expectations regarding our ability to obtain and maintain intellectual property protection and our ability to license additional intellectual property relating to our product candidatesfrom third pa

41、rties and to comply with our existing license agreements;our plans to research,develop,manufacture and commercialize our product candidates;the potential benefits of our commercial product and product candidates;the timing or likelihood of regulatory filings and approvals for our product candidates,

42、along with regulatory developments in the US,European Union(“EU”),the United Kingdom(“U.K.”)and other foreign countries;TM4Table of contentsthe size and growth potential of the markets for our commercial product and product candidates,if approved,and the rate and degree of market acceptance of our c

43、ommercial product andproduct candidates,including reimbursement that may be received from payors;our need for and ability to obtain additional funding,on favorable terms or at all,our plans to collaborate,or statements regarding our current collaborations with BioNTech SE(“BioNTech”)and others;our l

44、icense and option agreement with BioNTech,including our potential to receive milestone payments and royalties under the agreement;our ability to attract collaborators with development,regulatory and commercialization expertise;our ability to identify,recruit and retain qualified employees and key pe

45、rsonnel;our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately;the scalability and commercial viability of our manufacturing methods and processes;the success of competing therapies that are or may become available;whether we are classified as a

46、Passive Foreign Investment Company(“PFIC”),for current and future periods;additional costs and expenses related to our decision to voluntarily comply with certain U.S.domestic issuer reporting obligations before we are required to do so;andany other factors which may impact our financial results or

47、future trading prices of our American Depositary Shares(“ADSs”),and the impact of securities analysts reports on theseprices.Although we believe that the expectations reflected in these forward-looking statements are reasonable,these statements relate to our strategy,future operations,future financi

48、al position,future revenue,projected costs,prospects,plans,objectives of management and expected market growth,and involve known and unknown risks,uncertainties and other factors including,withoutlimitation,risks,uncertainties and assumptions regarding the impact of macroeconomic events,including in

49、flation,changes in interest rates,changes in trade policies,political changes,unfavorablegeneral market conditions and the impacts of the war in Ukraine,the conflicts involving Israel,and global geopolitical tensions,on our business,operations,strategy,goals and anticipatedtimelines,our ongoing and

50、planned preclinical activities,our ability to initiate,enroll,conduct or complete ongoing and planned clinical trials,our timelines for regulatory submissions and ourfinancial position that may cause our actual results,levels of activity,performance or achievements to be materially different from an

51、y future results,levels of activity,performance or achievementsexpressed or implied by these forward-looking statements.You are urged to carefully review the disclosures we make concerning these risks and other factors that may affect our business andoperating results in this Annual Report on Form 1

52、0-K.You are cautioned not to place undue reliance on these forward-looking statements,which speak only as of the date of this document.Exceptas required by law,we do not intend,and undertake no obligation,to update any forward-looking information to reflect events or circumstances.RISK FACTOR SUMMAR

53、YOur business is subject to a number of risks and uncertainties,including those risks discussed more fully in Part I,Item 1A.,Risk Factors in this Annual Report.These risks include,among others,thefollowing:We are an early commercial stage biopharmaceutical company and have incurred significant loss

54、es since our inception.We expect to continue to incur losses for the foreseeable future.AUCATZYL and any other product candidates,if approved,may fail to achieve the degree of market acceptance by physicians,patients,third-party payors and others in the medicalcommunity necessary for commercial succ

55、ess,thereby limiting our potential to generate revenue.If we are unable to fully develop our sales,marketing and distribution capability on our own,or enter into sales,marketing and distribution agreements with third parties,we may not besuccessful in commercializing AUCATZYL,or our other product ca

56、ndidates,if and when approved.Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.We will need additional funding to successfully commercialize AUCATZYL and to complete the development of and commercialize our

57、 other product candidates,which may not beavailable on acceptable terms,if at all.We have incurred substantial obligations under license and collaboration agreements,which could impair our flexibility and access to other capital and adversely affect our financial position,and our business would be a

58、dversely affected if we were unable to meet our obligations under these and similar future agreements.If we are unable to advance our product candidates through clinical development,obtain regulatory approval and ultimately commercialize our product candidates,or experience significantdelays in doin

59、g so,our business will be materially harmed.5Table of contentsOur proprietary,next-generation T cell programming technologies,our modular approach for engineering T cells and our manufacturing platform for our programmed T cell productcandidates,represent emerging approaches to cancer treatment that

60、 face significant challenges and hurdles.We collaborate with third parties in the research,development and commercialization of certain of our product candidates.If our collaborators do not perform as expected or if we are unableto maintain existing or establish additional collaborations,our ability

61、 to develop and commercialize our product candidates may be adversely affected.We may form or seek strategic alliances or enter into additional licensing arrangements in the future,and we may not realize the benefits of such alliances or licensing arrangements.Our future success is highly dependent

62、on the regulatory approval of our current clinical-stage programmed T cell product candidates and our preclinical programs.All of our productcandidates will require significant clinical or preclinical testing before we can seek regulatory approval for and launch a product commercially.Adverse side e

63、ffects or other safety risks associated with our product candidates could delay or preclude approval,cause us to suspend or discontinue clinical trials,cause us to abandonproduct candidates,could limit the commercial profile of an approved label,or could result in significant negative consequences f

64、ollowing any potential marketing approval.If the clinical trials of any of our product candidates fail to demonstrate safety and efficacy to the satisfaction of the Food and Drug Administration(“FDA”),the European MedicinesAgency(“EMA”)and the European Commission,or other comparable regulatory autho

65、rities,or do not otherwise produce favorable results,we may incur additional costs or experiencedelays in completing,or ultimately be unable to complete,the development and commercialization of our product candidates.We may not be able to successfully create our own manufacturing infrastructure for

66、supply of our requirements of programmed T cell product candidates for use in clinical trials and forcommercial sale.Our product candidates are biologics and the manufacture of our product candidates is complex and we may encounter difficulties in production,particularly with respect to processdevel

67、opment or scaling-out of our manufacturing capabilities.If we encounter such difficulties,our ability to provide supply of our product candidates for clinical trials or our products forpatients,if approved,could be delayed or stopped.We operate in a rapidly changing industry and face significant com

68、petition,which may result in others discovering,developing or commercializing products before or more successfully thanwe do.If we are unable to obtain and maintain patent protection for our T cell programming technologies and product candidates,or if the scope of the patent protection obtained is n

69、ot sufficientlybroad,our competitors could develop and commercialize technology and biologics similar or identical to ours,and our ability to successfully commercialize our technology and productcandidates may be impaired.As an English public limited company,certain capital structure decisions will

70、require shareholder approval,which may limit our flexibility to manage our capital structure.General market conditions and macroeconomic trends,including those driven by geopolitical tension,supply chain disruptions,market volatility,inflation,fluctuations in foreign currencyexchange rates,political

71、 changes,and changes in trade policies,among other factors,could materially and adversely affect our business,results of operations and financial condition.Failure or perceived failure to comply with existing or future laws,regulations,contracts,self-regulatory schemes,standards,and other obligation

72、s related to data privacy and security(including security incidents)could harm our business.Compliance or the actual or perceived failure to comply with such obligations could increase the costs of our products,limit their useor adoption,and otherwise negatively affect our operating results and busi

73、ness.6Table of contentsPART IItem 1.BusinessBusiness OverviewWe are an early commercial-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer and autoimmune diseases.On November8,2024,the U.S.Food and Drug Administration,or FDA,granted mar

74、keting approval for our first approved commercial product,AUCATZYL/obe-cel(obecabtagene autoleucel)for the treatment ofadult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia,or r/r B-ALL.We commercially launched AUCATZYL in the United States in January 2025,and we p

75、lan toinitiate sales of AUCATZYL/obe-cel in the European Union,or EU,and the United Kingdom,or UK,once regulatory approval is received.Marketing authorization submissions forAUCATZYL/obe-cel were accepted by the European Medicines Agency,or EMA,in April 2024 and the U.K.Medicines and Healthcare prod

76、ucts Regulatory Agency,or MHRA,in August 2024,andwe expect to receive notification of approval status from these authorities in the second half of 2025.AUCATZYL is a CD19-targeting programmed T cell investigational therapy with a CD19 binder designed to improve the efficacy and safety profile,as com

77、pared to other CD19 CAR Tchimeric antigen receptor T cell,or CAR T,therapies.Adult r/r/B-ALL is an extremely aggressive type of blood cancer with a high unmet medical need in the treatment of patients once they relapse,where historically patients suffer from poor outcomes.AUCATZYL is manufactured at

78、 our dedicated commercial manufacturing site,the Nucleus,in Stevenage,UK.If we receive approval tocommercialize AUCATZYL outside of the United States,we intend for the Nucleus to meet the global supply demands of AUCATZYL,with Cardinal Health serving as our commercial distributionpartner in the Unit

79、ed States.In addition to AUCATZYL/obe-cel for the treatment of adult r/r B-ALL,we are advancing obe-cel in other oncology indications including pediatric B-ALL and B-NHL,for which we haveinitiated Phase 1 studies.Obe-cel is also being developed for the treatment of autoimmune indications and we have

80、 initiated a Phase 1 study in patients with severe,refractory systemic lupuserythematosus(“SLE”).Using our broad suite of proprietary and modular T cell programming technologies,we are also developing five programs in seven hematological and solid tumor indications and oneautoimmune indication.We ar

81、e engineering precisely targeted,controlled and highly active T cell therapies that are designed to better recognize target cells,break down their defense mechanisms andattack and eliminate these cells.We believe our programmed T cell therapies have the potential to be best-in-class and offer patien

82、ts substantial benefits over the existing standard of care,includingthe potential for cure in some patients.Our T cell programming technologies allow us to tailor our therapies to address the specific disease we are targeting and introduce new programming modules into a patients T cells to givethose

83、 T cells improved properties to better recognize target cells and overcome fundamental disease defense mechanisms.Cancers in particular,thrive on their ability to fend off T cells by evadingrecognition by T cells and by establishing other defense mechanisms,such as checkpoint inhibition,and creating

84、 a hostile microenvironment.We believe our leadership in T cell programmingtechnologies will provide us with a competitive advantage as we look to develop future generations of T cell therapies targeting both hematological cancers,solid tumors and autoimmune diseases,including potential products tha

85、t could have a sufficient tolerability profile to enable use in outpatient settings.7Table of contentsOur PipelineOur current clinical-stage pipeline comprises five programs being developed in seven hematological and solid tumor indications and one autoimmune indication.Our current pipeline isbelow:

86、Our product pipeline is built on our core principles of modular innovation with protein-based cell programming focused on advanced targeting,pharmacological control and enhancement ofactivity.After identifying a target,we select the suite of programming modules that we believe is best suited to targ

87、et that particular disease based on the latest clinical data and the results of ourresearch.The particular modules selected may vary,and not every product candidate,including our current product candidates,contain all categories of modules.A viral vector is used to introducecombinations of these mod

88、ules into the DNA of the T cells,as depicted in the graphic below.The diagram below shows how our programming modules relate to our product candidates.Our programs have been highly tailored and specifically engineered via our proprietary modules,and have the potential to be truly differentiated asse

89、ts that could address limitations ofcurrent treatments and provide innovative options for patients.8Table of contentsOur StrategyOur strategic priorities include:Execute on the U.S.launch and commercialization of AUCATZYL/obe-cel for adult r/r B-ALLSubject to receiving regulatory approval,launch AUC

90、ATZYL/obe-cel for adult r/r B-ALL in the U.K.and European UnionDevelop obe-cel for treatment of potential additional indications,including LupusBuild our research and development pipelineBackground on T Cells and CancerCancers originate from individual cells that have developed mutations in essentia

91、l cellular programs,driving increased cell division and growth.A key control mechanism to detect andeliminate such cells is the patients own T cells.T cells are a type of white blood cells used by the human immune system to defend the body against infectious pathogens and cancerous cells.Usingtheir

92、T cell receptor like a molecular scanner,T cells are able to discriminate between normal human cells and ones that contain a mutation that alters their function.If the T cell recognizes an alteredcell,it becomes activated and kills that particular cell.For a cancer to grow to the detriment of the pa

93、tient,cancer cells evolve mechanisms to evade recognition by,or establish other defenses against,T cells.Cancer Immunotherapy and T cell TherapiesIn recent years we have seen the emergence of cancer immunotherapy,in which treatments harness the power of a patients immune system to combat their disea

94、se.Cancer immunotherapy treatment requires the activation and expansion of cancer-specific T cells,which kill cancer cells by recognizing antigen targets expressed on cancer cells.Studieshave shown that tumors develop escape mechanisms that prevent T cell-mediated destruction through immune checkpoi

95、nt proteins,which shut down anti-tumor immunity.Clinical trials have shownthat treatment with immune checkpoint inhibitors can restore T cell activity and results in durable clinical responses.Several anti-PD1 and anti-PD-L1 antibodies are approved for the treatment ofvarious solid tumors and Pembro

96、lizumab is also approved in relapsed/refractory classical Hodgkins disease or primary mediastinal B-cell lymphoma.However,none of the immune checkpointinhibitors are currently approved in other hematologic indications.While these approaches collectively represented major advances in cancer treatment

97、,they all lack active redirection of the patientsT cells to the cancer,eventually limiting clinical activity.More recently,redirected T cell therapies that are designed to give the patients T cells a new specificity to recognize cancer cells have been developed.The first approved product of thisclas

98、s is a bi-specific T cell engager called blinatumomab(Blincyto)from Amgen Inc.Blinatumomab targets the CD19 antigen on the surface of B cells and cancers derived from B cells.Blinatumomab is approved for the treatment of B-ALL.More recently,genetically programmed redirected T cell therapies have bee

99、n approved.These include the CD19 targeting therapiesKymriah,Yescarta,Tecartus,and Breyanzi,developed by Novartis AG,Kite Pharma,Inc.and Bristol Myers Squibb Inc.,respectively,for the treatments of B-ALL and B-NHL.All four ofthese therapies showed high response rates and,in a subset of patients,prol

100、onged treatment effects.For those patients experiencing a relapse,the common causes for relapse are insufficient survivalof the programmed T cells,loss of the CD19 target on the cancer cells and upregulation of checkpoint inhibitor PD-L1 on the cancer cells.In view of the limitations of current ther

101、apies,there remains a critical unmet medical need for improved T cell therapies.We believe that improving efficacy and durability over the productscurrently on the market or in development for the treatment of cancers requires addressing target antigen loss,countering checkpoint inhibition and addin

102、g novel targets to expand the range ofindications amenable to programmed T cell therapy.We believe our commercial product and our clinical-stage product candidates and our approach to T cell programming have the potential toaddress these limitations.Programmed T Cell TherapiesChimeric Antigen Recept

103、ors(“CARs”)We use CARs to reprogram our T cell product candidates.These receptors combine the tumor recognition domain of an antibody with the activation and costimulatory domains from the Tcell receptor to rearm a patients T cells to recognize and kill their cancer cells.9Table of contentsCAR T Cel

104、l Production We have developed our own proprietary viral vector and semi-automated cell manufacturing processes to engineer a patients T cells with the CAR and other programming modules.We believethat this autologous approach has the potential to be both the safest and most therapeutically effective

105、 approach to manufacturing CAR T cells.Limitations of Current T Cell ImmunotherapiesExisting T cell immunotherapies,including CAR T therapies,have shown significant efficacy in hematological malignancies;however,the extent and duration of the treatment effects anddisease remission are yet to be full

106、y defined.Optimizing the targeting module of a programmed T cell may enhance its effect and safety.Also,in response to targeted therapies,cancer cells oftenmutate and cease to express the antigen the therapy was designed to recognize.This loss of target antigen leads to patient relapse.Additionally,

107、numerous challenges,including lack of T cell persistence and upregulation of checkpoint inhibitors,represent significanthurdles that need to be addressed by new therapies.T cell immunotherapies also have the capacity to elicit toxicities including CRS,neurologic toxicity and the elimination of norma

108、l cells via on-target off tumor recognition.Further,manufacturing T cells can be prohibitively costly if the manufacturing process is not appropriately designed to support parallel processing and automation.Finally,realization of the potential of this approach across a broad range of solid tumor typ

109、es will require multiple technology solutions in order to address limitations of the current generation oftherapies.10Table of contentsEmerging Promise of T Cell Immunotherapies for the Treatment Autoimmune DiseasesAutoimmune diseases are the result of an immune system that is overactive,causing it

110、to attack and damage the patients own tissues.Autoimmune diseases can affect multiple organsthroughout the body and can be life threatening in some cases.The presence of autoreactive B cells that produce autoreactive antibodies,antibodies that attack the bodys own tissues,are a commonfeature of thes

111、e diseases.As such,therapeutic approaches that deplete B cells have had some clinical success.These B cell depletion approaches,such as the antibodies that target CD20(Rituximab,Ocrelizumab and Ofatumumab,)and BAFF(Belimumab)are approved for the treatment of autoimmune diseases including systemic lu

112、pus erythematosus and multiple sclerosis.These antibody-basedapproaches have shown limited efficacy,typically limiting the progression of the autoimmune disease rather than ameliorating the disease completely.These therapies also require long-termadministration and can have serious side effects.Rece

113、ntly a small academic clinical trial conducted by Mackensen and colleagues from the University of Erlangen in Germany has shown that targeting CD19 with CAR T therapies canprofoundly improve outcomes for patients with lupus and other autoimmune diseases.CD19 is a B cell specific antigen that is high

114、ly expressed on B cells including malignant B cells that causecancers like B-ALL and autoreactive B cells that are a common feature of autoimmune disease.In this academic clinical trial,treatment of 15 autoimmune disease patients with a single dose ofautologous CD19 CAR T cells resulted in rapid and

115、 durable responses in patients.These patients all had advanced disease,with multi-organ involvement and were refractory to current therapies.Thetreatment showed potential transformational clinical benefit,with all patients in remission or with major reductions in symptoms with a median follow up of

116、15 months.Toxic effects weremanageable and mostly mild.CD19 CAR T cell therapy shows the potential for superior efficacy compared to B cell depleting antibodies.It may be possible that CD19 is a better target than CD20 or BAFF,as it isexpressed more broadly on the autoreactive plasma cells and plasm

117、a blasts as well as B cells.Additionally,CAR T cells may be better at depleting the B cells than the antibodies,as they canpenetrate into all tissues including some that antibodies cannot reach.The future promise of CAR T cell therapy for autoimmune diseases will be driven by efficacy,safety and cos

118、t effectiveness.Existing CD19 CAR T cell therapies,are effective at treating B-cell malignancies;however,the extent and duration of the treatment effects and disease remission as well as the potential for toxicities including CRS and neurologic toxicity varies considerablybetween the different appro

119、ved treatments.Differences in efficacy and safety are likely to be seen between different CD19 CAR T cell therapy approaches for Autoimmune diseases and optimizingthe CD19 targeting module may be important for enhancing efficacy and safety.Further,manufacturing T cells can be prohibitively costly if

120、 the manufacturing process is not appropriately designedto support parallel processing and automation.Our Solution:Advanced T Cell ProgrammingOur technological approach is the development of advanced T cell engineering components designed to directly address clinical challenges.A focus in our early-

121、stage pipeline isincorporation of multiple components in a single product.Advanced Targeting TechnologiesWe have developed advanced antigen targeting technologies to improve the ability of our programmed T cell therapies to selectively identify and target cancer cells and to deliver a sustainedanti-

122、tumor effect.These targeting technologies include fast off-rate CARs,novel targets,high avidity spacers,dual-targeting and pattern recognition.Fast Off-Rate CARsWe have designed programmed T cells with fast off-rate binders.These fast off-rate kinetics are similar to the behavior of naturally occurr

123、ing T cells.Obe-cel has this enhanced kineticprofile,which,when compared to data reported for other CAR T cell product candidates in clinical development for ALL that use high affinity binders,appears to result in reduced Cytokine ReleaseSyndrome and in increased T cell engraftment.We use Fast Off-R

124、ate CARs targeting CD19 in our obe-cel,AUTO1/22 and AUTO8 programs.Dual-Targeting CARsRelapse due to target antigen loss or down regulation is a major cause of treatment failure in CAR T cell therapy.We have developed product candidates that target two antigens on a cancercell and are designed to re

125、duce the chances for relapse due to antigen escape.Evidence suggests that it may also improve a response in those patients with low levels of expression of a target antigenon their cancer cells.We use Dual Targeting CARs in our AUTO1/22 and AUTO8 programs.11Table of contentsPharmacological Control o

126、f T Cell ActivityManagement of toxicity is a critical step in the successful application of programmed T cell therapies.We have developed multiple technologies designed to pharmacologically control T cellactivity in the event a patient suffers certain serious adverse events related to the T cell the

127、rapy.Safety switches are designed to selectively eliminate the programmed T cells following administrationof a pharmacological agent,whilst tuneable or controllable CAR T cells allow the activity of T cell therapy to be dialed down following administration of a pharmacological agent.Rituximab Safety

128、 Switch(RQR8)The RQR8 safety switch is designed to selectively eliminate the programmed T cells by the administration of the commercially available monoclonal antibody rituximab.Once administered,rituximab binds to the engineered CD20 epitopes on the surface of the programmed T cell and triggers cel

129、l death.We use the RQR8 safety switch in our AUTO4,AUTO5 and AUTO6NG programs.Rapamycin Safety Switch(RapaCasp9)The RapaCasp9 safety switch is designed to selectively eliminate the programmed T cells by the administration of the commercially available drug rapamycin.Once administered,rapamycinhetero

130、dimerises caspase 9 via FRB and FKBP to activate a cell death cascade and selectively eliminate the programmed T cells.Tetracycline Controllable CAR(TetCAR)TetCAR is a controllable CAR T cell system designed to reversibly dampen the activity of the programmed T cells by the administration of the com

131、mercially available antibiotic tetracyclineto a patient.Once administered,tetracycline temporarily dislocates the CAR signaling domain from the cancer antigen binding domain leading to deactivation of the T cell therapy.Activity is thenrestored on clearance of the pharmacological agent from the pati

132、ent.Tumor Microenvironment ShieldingTumor cells and other cells in the tumor microenvironment can debilitate anti-tumor immune responses.Proteins expressed on tumor cells can trigger inhibitory receptors on T cells to blocktheir ability to eliminate the tumor.Secretion of TGF by the tumor and other

133、cells can shut down the activity of a T cell therapy.We have developed technologies designed to shield our programmedT cells from these immunosuppressive pathways.Checkpoint Shielding(dSHP2)Immune checkpoint receptors act through a common signaling pathway inside the T cell that prevents normal T ce

134、ll activation.We have developed a modified version of an adaptor protein,SHP2,that in preclinical studies has been shown to efficiently counteract the inhibition of T cells resulting from the PD-L1/PD-1 interaction.In addition,it is designed to simultaneously disarmmultiple inhibitory receptors on t

135、he cancer cell.We use the dSHP shielding module in our AUTO6NG program.Enhanced ActivityOne of the challenges of targeting some solid tumors is the lack of such easily accessible stimulation for programmed T cells,leading to poor persistence and a weak anti-tumor activity.Co-administration with cyto

136、kines can boost T cell activity and persistence.Certain cytokines can potentiate the anti-tumor of the T cell therapy by recruiting and activating other immune cells to kill thetumor.However,systemic or local administration of cytokines can be toxic,therefore we have developed programming modules th

137、at are designed to harness the enhanced activity of cytokineswhilst avoiding the potential for toxicities.Chimeric Cytokine Receptors(CCRs)The CCR is a programming module that is designed to deliver a cytokine signal directly inside T cells without administration or secretion of cytokines themselves

138、.We use proteins from anantibody structure to stably heterodimerize two cytokine signaling domains together to deliver a proliferative and survival signal into our T cells.Preclinical data has demonstrated the potential forthe CCR to improve the persistence and activity of CAR T cell therapy against

139、 solid tumors.We use the CCR enhanced activity module in AUTO6NG.Host Immune System Recruitment(ssIL12)IL-12 is a potent anti-tumor cytokine that mediates the activity of many different anti-tumor immune cells.The majority of clinical studies involving treatment of patients with IL-12 wereassociated

140、 with severe systemic side effects mediated by high levels of IFN.Our ssIL12 module is designed to secrete very low levels of IL-12 from our T cells and our preclinical data demonstratesthe potential for ssIL12 to provide anti-tumor without systemic toxicity.12Table of contentsEngineering survival s

141、ignal(Fas-TNFR)CAR T cells have shown remarkable efficacy against hematological cancers,but their effectiveness in solid tumors has been limited by inhibitory factors expressed by the tumor or itsmicroenvironment.One such inhibitory factor is Fas ligand(“FasL”),which binds to the Fas receptor(CD95)o

142、n the surface of an activated T cell and triggers the CAR T cell to die by apoptosis.OurFas chimeras consist of the extracellular domain of Fas fused to the intracellular domain from different TNF receptor superfamily members.Expression of these chimeras in a CAR T cell not onlyblocks apoptosis trig

143、gered by FasL,but results in co-stimulation,which promotes CAR T cell survival and proliferation.Our Commercial Product:AUCATZYL for Adult r/r B-ALLAUCATZYL/obe-cel,formerly known as AUTO1,is a gene therapy product consisting of autologous T cells that are transduced with a lentiviral vector to expr

144、ess a novel anti-CD19Chimeric Antigen Receptor(CD19(CAT)CAR).The transduced T cells express second-generation CARs in which the CD19 CAR construct uses 41BB-and CD3-endodomains.CD19 is an ideal target for a CAR T cell therapy as it is a cell surface marker for B-precursor cells and B-lymphocytes tha

145、t is present on most B cell malignancies.CD19 is also a cell surfacemarker expressed broadly on the autoreactive B-cells and plasma cells that are associated with autoimmune diseases such as lupus.Upon CD19 directed CAR T cell therapies,it also leads to B-cellaplasia which can be used as a pharmacod

146、ynamic marker.CD19 CAR T cell therapies have proven effective in treating B-cell leukemias,B-cell lymphoma and early evidence suggest they areeffective in treating b-cell mediated autoimmune diseases.Efficacy is dependent on engraftment and expansion of the CAR T cells.However,rapid activation and e

147、xpansion of CAR T cells can resultin CRS and/or ICANS,which in some cases can be life-threatening,particularly for elderly patients and patients with comorbidities that have a poor tolerance for toxicity.Furthermore,excessiveactivation of CAR T cells can lead to cell exhaustion and limit their engra

148、ftment and expansion,which may impact the initial efficacy and durability of therapeutic effect.Obe-cel is an autologoustherapy in which a patients T cells are genetically modified to express a novel CD19-specific binder designed to reduce side effects observed with this class of therapeutics.AUCATZ

149、YL/obe-cel recognizes and interacts with the CD19 target with a fast off-rate enabled by the novel CAT scFv binding domain.This property allows the AUCATZYL/obe-cel cells toefficiently recognize target cells,inject cytotoxic proteins to initiate the natural self-destruction process present in all hu

150、man cells and then rapidly disengage from them in order to engage the nexttarget cell,a process also known as serial killing.Rapid disengagement from the target antigen is expected to minimize excessive activation of the programmed T cells,reduce toxicity and may alsoreduce T cell exhaustion.The US

151、FDA granted marketing approval for obe-cel for the treatment of adult patients with r/r B-ALL on November 8,2024 under the brand name AUCATZYL.Marketing authorizationapplications(“MAA”)for AUCATZYL/obe-cel in adult r/r ALL are being reviewed by the regulators in both EU and the U.K.,with a submissio

152、n to the EMA accepted in March 2024,and asubmission accepted by the U.K.MHRA in August 2024.We expect to receive notification of approval status from these authorities in the second half of 2025.Clinical Development of Obe-cel in Adult ALLBackground of Adult ALLObe-cel was tested in a Phase 1b/2 cli

153、nical trial for the treatment of adult ALL,which according to the American Cancer Society is predicted to affect approximately 6,500 adults in theUnited States in 2023.Combination chemotherapy enables 90%of adult patients to experience complete remission(“CR”).However,the majority of these remission

154、s are not long-lasting in adultpatients.Despite this initial CR,and in contrast to pediatric ALL,the prognosis of adult ALL is still poor and has not changed significantly during the last two to three decades,with long-termremission rates limited to 30-40%.Approximately 50%of all adult ALL patients

155、will relapse,and data from the Medical Research Councils UKALL12/ECOG 2993 study,published in 2007,foundthat five-year overall survival(“OS”),rate in adults who relapse following standard multi-agent chemotherapy is 7%.The only curative option for relapsed or refractory ALL consists of achieving ase

156、cond CR by salvage therapy followed by an allogeneic hematopoietic stem cell transplant(“allo-HSCT”).Without allo-HSCT,a subsequent relapse occurs in nearly all patients.However,less thanhalf of patients achieve a second CR,and therefore only a subset will be eligible for this procedure.Even then,le

157、ss than one-third of patients receiving the transplant are expected to sustain long-termdisease-free survival.Further,allo-HSCT is associated with severe morbidity and significant mortality.Many patients with relapsed or refractory ALL will have been maximally treated withchemotherapy,and often do n

158、ot achieve a second CR with standard-of-care chemotherapy in order to be eligible for allo-HSCT.13Table of contentsTwo targeted immunotherapies have been approved in a number of jurisdictions,including the United States and the EU,for the treatment of adult ALL:blinatumomab and inotuzumabozogamicin.

159、Both of these therapies achieve high CR rates,but durability is limited.In a randomized Phase 3 clinical trial of blinatumomab in heavily pretreated B-cell precursor ALL,theblinatumomab arm achieved a CR rate of 44%,of which 76%also achieved MRD-negative CR,and the median duration of remission was 7

160、.3 months.The median OS in those patients,thoughsignificantly improved compared to chemotherapy,was still only 7.7 months.Similarly,in a Phase 3 clinical trial of inotuzumab ozogamicin,a higher percentage of patients achieved MRD-negativeCR when treated with inotuzumab compared to standard-of-care c

161、hemotherapy,but the median duration of remission was 4.6 months and median OS was 7.7 months.On October 1,2021 the FDA approved the use of the CAR T cell therapy brexucabtagene autoleucel(“Tecartus”)for adults with B-cell precursor ALL that has not responded to treatment(refractory)or has returned a

162、fter treatment(relapsed).The European Commission approved Tecartus for adults aged 26 and over with relapsed or refractory B-cell precursor ALL in September 2022.On November 8,2024 the FDA approved the use of obe-cel for the treatment of adults with r/r B-ALL.Obe-cel Phase 1b/2 Clinical Trial in Adu

163、lt ALL(FELIX Trial)We initiated the FELIX study,a Phase 1b/2 clinical trial of obe-cel for the treatment of adult r/r B-Acute Lymphoblastic Leukemia,in 2020.Most recently the data were published in the NewEngland Journal of Medicine in December 2024.The published data were from a pooled analysis of

164、data from all patients across all cohorts in the FELIX Phase 1b/2 study.Of the 153 r/r B-ALL patients enrolled patients in the FELIXstudy,127(83.0%)received at least one obe-cel infusion and were evaluable.Eligible patients underwent leukapheresis,and bridging therapy,except blinatumomab,was permitt

165、ed at theinvestigators discretion.Obe-cel was administered in a bone marrow(“BM”)burden adjusted split dose following lymphodepletion,with a BM mandated prior to lymphodepletion to guide dosing.The second obe-cel dose was given in the absence of severe/unresolved toxicity.The primary end point was o

166、verall remission(“CR/Cri”).In the pivotal cohort of patients,(cohort IIA(n=94),the CR/CRi for patients who received at least one infusion of obe-cel was76.6%.Across all infused patients(n=127),of the 91/127 with 5%BM blasts pre-lymphodepletion,the CR/CRi was 74.7%.Median response duration for all in

167、fused patients was 21.2 months.Median event-free survival(EFS)was 11.9 months and the estimated 6-and 12-month event-free survival rates were 65.4%and 49.5%,respectively.BM burden pre-lymphodepletion correlated withmedian event-free survival;patients with low(75%blasts)BM burden had event-free survi

168、val rates at 12 months of 68.0%,54.9%and25.0%,respectively.Median overall survival(“OS”)was 15.6 months and estimated 6-and 12-month overall survival rates were 80.3%and 61.1%,respectively.BM burden pre-lymphodepletion correlated withoverall survival;patients with low,intermediate,and high BM burden

169、 had an overall survival rate at 12 months of 71.5%,58.7%and 55.0%,respectively.BM burden before enrollment alsoinfluenced event-free and overall survival.Of the 127 patients infused(pooled across all study cohorts),99 patients responded.Of the responders,18 patients(18.2%)proceeded to allo-Stem Cel

170、l Transplant(“allo-SCT”)while inremission at a median of 101 days post-obe-cel infusion.In 6/18(33.3%),this was a second allo-SCT.Of 11 patients who had persisting CAR T cells before allo-SCT,and who had samples availablepost,none had CAR T cells detected following allo-SCT.There was no difference i

171、n event-free and overall survival observed between patients who received allo-SCT and those who did not.Median duration of CAR T persistence by droplet digital PCR(ddPCR)in peripheral blood was 17.8 months.Obe-cel was associated with minimal immunotoxicity.CRS and Immune effector cell-associated neu

172、rotoxicity syndrome(“ICANS”)rates(Grade 3)were 2.4%and 7.1%,respectively.Overall,87(68.5%)patients developed CRS,and 29(22.8)developed ICANS.Severe ICANS post-obe-cel were seen as largely limited to patients with high BM burden pre-lymphodepletion.Intensive care unit(ICU)admissions occurred in 20(15

173、.7%)patients for a median of 5.5 days(range,137)of which 7/20 were admitted due to immunotoxicity management(5 ICANS,2 CRS).Obe-cel Phase 1 Clinical Trial in Adult ALL(ALLCAR19 Trial)In the first quarter of 2018,our academic partner University College London(“UCL”)initiated a single-arm,open label,m

174、ulti-center Phase 1 clinical trial of obe-cel,named the ALLCAR19trial,in patients aged 16 to 65 years with high-risk,relapsed or refractory CD19 positive B-lineage ALL.The clinical trial was conducted at sites in the United Kingdom.The trial enrolled patientswith a high tumor burden;45%of treated pa

175、tients had 50%or greater bone marrow blasts.In the trial,20 patients received obe-cel;product for 14 of those patients was manufactured using a semi-automated,fully-enclosed process.The therapy was well tolerated,with no patients experiencing Grade 3 or higher CRS.Three patients(15%),all of whom had

176、 high leukemia burden(50%blasts),experienced Grade 3 ICANS that resolved swiftly with steroids.Of the 20 patients evaluable for efficacy,17 patients(85%)achieved minimum residual disease(“MRD”)-negative CR at one month.14Table of contentsA pooled analysis of long-term follow-up data from ALLCAR19 an

177、d FELIX Phase 1b Studies were presented at the ASH,meeting in December 2023.Data from the pooled analysis of r/r B-ALL patients(n=36)treated with obe-cel in the ALLCAR19 and FELIX Phase 1b studies showed high remission rates of 81%(29/36).After a median follow-up of 3 years and without subsequenttra

178、nsplant,41%of patients continued in complete remission.The estimated EFS rate with censoring of subsequent transplant or new treatment was 45%at 36 months;all patients in ongoingremission were MRD negative at last assessment and median duration of response was not reached.Regulatory Status and Plans

179、Obe-cel has received a number of designations from regulatory authorities,as follows:FDA orphan drug designation for the treatment of ALL(October 2019),EMA PRIME designation(March 2021),MHRA ILAP designation(June 2021),European Commission orphan drug designation(March 2022),and FDA RMAT designation(

180、April 2022).The US FDA granted marketingapproval for obe-cel on November 8,2024 under the brand name AUCATZYL for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia(r/r B-ALL)without the need for a Risk Evaluation and Mitigation Strategy(REMS).T

181、he approval is based on data from the Phase 2 cohort of FELIX study.MAAs for obe-cel in r/r B-ALL are beingreviewed by the regulators in both the EU and the UK,with a submission to the EMA accepted in March 2024,and a submission accepted by the U.K.MHRA in August 2024.Based on priorregulatory timeli

182、nes,we expect to hear from the MHRA and EMA regarding potential marketing approvals in the second half of 2025.Commercialization Strategy for AUCATZYLThe U.S.FDA has granted marketing approval for AUCATZYL for the treatment of patients with r/r B-ALL.We are now in the process of launching the produc

183、t in the US.In addition to thestandard sales&marketing elements and medical affairs activities required to successfully commercialize an oncology/hematology product,there are several additional requirements needed forcommercializing CAR-T cell therapies.This required several bespoke elements,includi

184、ng the processes for distribution,patient scheduling,center engagement and service hub to be established.It isa requirement that the product is administered only by authorized centers that are specialized in hematology and have the necessary infrastructure and capabilities for administering CAR-T th

185、erapies.We achieved our target 33 centers fully authorized to deliver AUCATZYL by end of January 2025,covering 60%of the accessible patient population,and this number of centers will steadily increasewith the expectation it will be over 50 centers by mid-2025.We expect to complete authorization of 6

186、0 treatment centers,covering approximately 90%of the target patient population,by the end of2025.In December 2024,the National Comprehensive Cancer Network,or NCCN,added AUCATZYL to its Clinical Practice Guidelines in Oncology,or NCCN Guidelines,for the treatmentof adult r/r B-ALL.The NCCN is a not-

187、for-profit alliance of 30 leading cancer centers devoted to patient care,research,and education.The NCCN Guidelines are a comprehensive set of guidelinesdetailing the sequential management decisions and interventions that currently apply to 97%of cancers affecting patients in the U.S and are intende

188、d to ensure that all patients receive preventive,diagnostic,treatment,and supportive services that reflect the latest evidence in oncological patient care.We have retained worldwide commercial rights for AUCATZYL.We plan to expand our global commercialization capabilities over time such that we are

189、able to commercialize any productcandidate in a broader number of countries over time,but with a focus on achieving an early presence in the U.S.,U.K.and parts of Europe,i.e.countries where we expect to obtain a regulatoryapproval.We may pursue strategic collaborations with third parties in order to

190、 maximize the commercial potential of AUCATZYL.Under the terms of the License and Option Agreement withBioNTech,BioNTech has certain options to co-promote or co-commercialize AUTO1/22 and AUTO6NG.We generally expect to launch any of our products that receive regulatory approval in theUnited States f

191、irst,followed by the U.K.,EU and subsequently in other major markets.The product option for AUTO1/22 was not exercised and has expired as of February 8,2025.See“RiskFactorsRisks Related to our Intellectual PropertyThird parties may initiate legal proceedings alleging that we are infringing their int

192、ellectual property rights,the outcome of which would beuncertain and could significantly harm our business.”Our Manufacturing and Logistics CapabilitiesWe are devoting significant resources to process development and manufacturing in order to optimize the safety and efficacy of AUCATZYL,to ensure hi

193、gh quality and reliable productsupply to patients,as well as to reduce our per unit manufacturing costs and time to market for AUCATZYL and any of our programmed T cell product candidates for which we obtain regulatoryapproval.The manufacture and delivery of programmed T cell therapies to patients i

194、nvolves complex,integrated processes,including harvesting T cells from patients,manufacturing viral vectors withnucleic acid content encoded with our programming modules,manufacturing programmed T cells using the viral vectors ex vivo,multiplying the T cells to obtain the desired dose,and ultimately

195、infusing the T cells back into a patients body.15Table of contentsCommercial success in T cell therapies requires a manufacturing process that is reliable,scalable and economical.We have established a manufacturing process that is scalable and serves asa manufacturing platform designed to support ra

196、pid development of our programmed T cell therapy product candidates through clinical trial phases and regulatory approval processes.We are using asemi-automated,fully enclosed system for cell manufacturing,which is designed to provide a common platform suitable for manufacturing all of our product c

197、andidates.This platform allows forparallel processing having the ability to scale for commercial supply in a controlled environment at an economical cost.We have established reliable and consistent viral vector production and viraltransduction processes further,also a key to our process reproducibil

198、ity and reliability.Our manufacturing and logistics process is designed to ensure that product integrity is maintained during shipment along with accurate tracking and tracing of shipments.We are expandinginternal manufacturing and supply capabilities as well as the use of expert service providers o

199、n maturing our vein-to-vein logistics and our gradual capacity expansion in support of commercialoperations.Chain of identity and chain of custody electronic systems are now in place to ensure transport and processing reliability and further adding to patient safety.Our manufacturing and commerciali

200、zation strategy requires a fully integrated vein-to-vein product delivery cycle.We believe having established manufacturing processes suitable forcommercialization early in the development of AUCATZYL will allow us to focus on expanding manufacturing capacity during our early commercial launch needs

201、.Over time,we expect to establishregional manufacturing hubs to meet projected near-,mid-and long-term commercial product requirements for commercialization.Our first purpose-built facility,the Nucleus,is located inStevenage,U.K.This facility,which has a global reach,can meet our near and mid-term c

202、linical and commercial needs allowing ample time for expanding our manufacturing footprint.Our plan is toestablish our manufacturing infrastructure in a manner that would minimize logistical complexities and costs for all regions going forward.The licensure and commercial supply of our cell products

203、 will be from our 70,000 square foot facility called the Nucleus,in Stevenage,United Kingdom.We believe this facility,which has aglobal reach,can meet our near and mid-term clinical and commercial needs allowing ample time for expanding our manufacturing footprint.In March 2024,following the most re

204、cent GMPinspection by the MHRA in February 2024,the Nucleus facility obtained a Manufacturers Importation Authorization(MIA)together with the accompanying GMP certificate.These licenses enableus to manufacture both commercial and clinical autologous drug products in the facility.The Nucleus provides

205、 multiple clean rooms,QC labs,warehouse and administrative space and is being fittedout in a phased manner as demand requires.At full capacity,we expect the Nucleus facility to provide manufacturing capacity for approximately 2,000 batches annually,Additional fallow space forthe expansion of manufac

206、turing capacity is available if required.Our plan is to establish our manufacturing infrastructure in a manner that would minimize logistical complexities and costs for allregions going forward.We believe our scalable closed-system manufacturing process,along with our proprietary and modular T cell

207、programming technologies,would be challenging and costly for potentialcompetitors to replicate.Our Manufacture and Delivery PerformanceData on manufacturing and delivery performance for obe-cel in the FELIX clinical trial were presented at the 2023 ASCO Annual Meeting in June 2023,with updated data

208、presented at theASH Annual Meeting in December 2023.The FELIX study successfully demonstrated the robust operability of obe-cel manufacturing,QC and logistics processes,meeting target V2C(time fromleukapheresis to quality release)and V2D(time from leukapheresis to delivery of product to the hospital

209、).Median V2C and V2D times were 21 and 24 days,respectively.All apheresis startingmaterial was successfully processed despite the multitude of constraints posed by the COVID-19 pandemic.In total,96%of manufactured obe-cel batches reached their target dose of 410 x 106 CART cells.Further optimization

210、 and improvements made during the study increased reliability,consistency,and precision of the manufacturing process,and supported the development of the Nucleusmanufacturing facility with greater production capacity that aims to achieve a 95%manufacturing success rate with 15-day V2C times.Manufact

211、uring Agreements with Third PartiesWe obtain viral vector for commercial supply of AUCATZYL and for late stage clinical trials from our partner AGC Biologics.We also have manufacturing agreements with Kings CollegeLondon for early phase vector manufacturing,and some internal capability to produce ve

212、ctor for early and late-stage trials.All vector manufacturing is done in accordance with current GoodManufacturing Practice(“cGMP”)in compliant manufacturing facilities.The manufacturing agreements governing the external supply arrangements also provide for access to services includingquality manage

213、ment systems,qualified persons for product release,office space,frozen storage and warehousing services.16Table of contentsIn March 2018,we entered into a strategic,long-term supply agreement with Miltenyi Biotec GmbH(“Miltenyi”),for the supply of Miltenyis CliniMACS Prodigy instruments,reagents and

214、disposables for the manufacture of our programmed T cell therapies,including for commercial production of AUCATZYL as well as for preclinical and clinical use,as well as support services.Thesupply agreement sets forth procedures to ensure continuity of supply to us of Miltenyis products,both during

215、the clinical phase and any future commercial phase of our product candidates.After theinitial ten-year term of the agreement,we have two separate options to renew the agreement,each for an additional five-year term.The supply agreement contains customary termination provisions,allowing for terminati

216、on by a party upon the other partys uncured material breach,upon the other partys bankruptcy or insolvency or upon the other party being subject to an extended period offorce majeure events.We may also terminate the supply agreement upon advance written notice,if we decide to suspend or discontinue

217、the development or commercialization of our productcandidates.The supply agreement is governed under the laws of Germany.CompetitionThere are two direct in class competitors to AUCATZYL approved for the treatment of adult patients with r/r B-ALL:the autologous CAR therapies Tecartus and Kymriah.Teca

218、rtus isapproved for use in adult B-ALL and Kymriah is approved for use in adolescents and young adults,(i.e.,patients up to the age of 25).We believe obe-cel has a differentiated safety profile and showspotential for longer term outcomes when compared to these current approved therapies.In addition,

219、it is possible that companies could take other autologous CAR T cell products forward in adult ALL or allogeneic“off-the-shelf”CAR T cell therapies could be developed whichwould be considered direct competitors.Allogeneic products are in early development in indications other than B-ALL,and,because

220、these products are not made from the patients own cells,theymight be more convenient to deliver,without the need to wait for a product to be manufactured(typical manufacturing times for autologous products are currently 18-25 days).However,this class ofproduct has not shown the same levels of durabl

221、e activity and the products in clinical trials are therefore likely to require periodic repeat dosing as opposed to autologous products,which allow for thetherapy to be given as a one-time treatment.Our Product Candidates for the Treatment of Hematological Cancers and Autoimmune DiseasesOur clinical

222、-stage product candidates targeting hematological cancers are obe-cel,AUTO1/22,AUTO4 and AUTO8.We have an additional hematological product candidate,AUTO5,inpreclinical development.Additionally,obe-cel is also being explored as a potential therapeutic approach targeting certain autoimmune diseases.O

223、be-cel for the Treatment of Pediatric ALL,B-NHL and other B-cell malignanciesIn addition to AUCATZYL/obe-cel for the treatment of adult r/r B-ALL,we are advancing obe-cel in other oncology indications including pediatric B-ALL and B-NHL,for which we haveinitiated Phase 1 studies.Background of Pediat

224、ric ALLAccording to the American Cancer Society,B-cell ALL is most common in childhood,peaking between two and four years of age.As per the National Cancer Institute Surveillance,Epidemiology and End Results statistics database,there are approximately 3,400 new cases of pediatric ALL diagnosed in th

225、e United States each year.The current standard of care for both pediatric and adult B-cell ALL patients is a standard regimen of combination chemotherapy.Pediatric patients typically respond well to the complexfirst-line chemotherapy treatment.According to the American Cancer Society,the five-year s

226、urvival rate for children with B-cell ALL is more than 85%overall.However,10 to 20%of pediatric B-cell ALL patients relapse with chemotherapy-resistant disease.These patients are re-treated with intensive chemotherapy,and those that respond may proceed to receive an allogenic stem celltransplant(“SC

227、T”).However,SCT can be associated with significant long-term morbidity due to the risk of developing graft-versus-host disease(“GVHD”),and treatment-related mortality,althoughthe risk of death have declined with better post-transplant management.Patients with high-risk clinical or genetic features i

228、ncluding gene abnormalities,as well as those who have an inadequate response to initial chemotherapy,may not respond well with thecurrent available treatments for B-cell ALL(including SCT),some of these patients will have a five-year OS rate of approximately 15%.Additionally,long-term survival rates

229、 are only approximately10 to 20%among patients receiving a second SCT and negligible in those unable to proceed to a second transplant.There is still a significant unmet medical need in pediatric patients with high-risk relapsed or refractory B-cell ALL.CD19 CAR T cell therapies have been developed

230、for these patients.Theapproved CD19 CAR T therapy,Kymriah,has shown approximately 80%of complete molecular response rate.However,at six months after treatment,approximately 40%of the patients relapsedand the majority of the relapses were CD19 negative disease,with approximately two-thirds of relapse

231、s determined to have been due to loss of CD19 on the target cells in one study.17Table of contentsCD19 CAR T cell therapies have been tested in pediatric ALL patients and have shown sustained responses without allo-HSCT.In adult ALL,however,one of the major challenges has beensevere toxicity,includi

232、ng death due to CAR T cell-mediated toxicity observed in the clinical trials of these products.Obe-cel has been designed to reduce toxicity but still sustain durable CRs.Obe-cel Phase 1 Clinical Trial in Pediatric ALLThe CARPALL trial was initiated by UCL in the second quarter of 2016 and is a singl

233、e-arm,open label,multi-center Phase 1 trial enrolling patients aged 24 years or younger with high-riskrelapsed or refractory CD19 positive B-lineage ALL.The main objective of the trial is to evaluate the safety and efficacy of obe-cel when administered at a single dose of 1 million cells/kg.The tria

234、lhas completed enrollment with obe-cel.However,the extension arm is now open,and treating pediatric ALL patients with AUTO 1/22As of the final data cut-off date of November 22,2019,the obe-cel arm of the CARPALL trial had enrolled a total of 25 patients,in two cohorts;one cohort utilized a manual ma

235、nufacturingprocess(cohort 1)and one cohort utilized a semi-automated fully enclosed manufacturing process(cohort 2).Product was generated for 14 of 17 patients in cohort 1 and the median follow-up for the14 treated patients was 23 months.Seven patients were treated in cohort 2.The aim of cohort 2 wa

236、s to increase feasibility of manufacture at scale;one patient died before infusion and product wasgenerated for 100%of patients.Median follow-up for patients in cohort 2 was seven months.None of the patients experienced Grade 3 or higher CRS and one patient out of 21 patients(5%)experienced Grade 4

237、neurotoxicity,which was deemed more consistent with fludarabine thanCAR-associated neurotoxicity.Two patients experienced Grade 5 sepsis and death,one in the context of progressive disease and the second was considered related to obe-cel.This patient was inMRD-negative CR and had ongoing Grade 4 cyt

238、openia associated with resistant HSV encephalitis.Thirteen patients experienced Grade 4 cytopenias that were ongoing at day 28.Nineteen of 21treated patients(90%)achieved molecular CR at post-infusion.Consistent with preclinical results,CAR T cell expansion and persistence was excellent and CARs wer

239、e detectable by flow for up to 36 months in four patients in cohort 1 who had ongoingresponses beyond 12 months.Persistence was noted in 15 of 21 patients at last follow-up,up to 36 months.All of the patients in cohort 2 achieved molecular CR at one month post-infusion.For cohort 1,with a median fol

240、low-up of 23 months,the OS at six and 12 months was 86%and 71%,respectively,and event-free survival at six and 12 months was 71%and 54%,respectively.In cohort 2,at a median follow-up of 7 months,five patients remain in complete molecular remission and two patients relapsed.Five of eight evaluable re

241、lapses in cohort 1 and cohort 2combined were due to CD19 negative escape.In December 2023,Autolus initiated a phase 1 study to evaluate the safety and efficacy of obe-cel in pediatric patients with r/r B-ALL and r/r B-NHL.This is a single-arm,open label,multi-center trial enrolling patients aged 18

242、and younger.The study is currently enrolling patients.Obe-cel Phase 1 Clinical Trial in other B-cell malignancies(ALLCAR19 and CAROUSEL Trials)The ALLCAR19 clinical trial has also been expanded to include three additional cohorts with a total of 40 patients:10 patients with r/r DLBCL(including trans

243、formed FL,but not Richters transformation);10 patients with relapsed or refractory B-cell CLL/small lymphocytic leukemia;and20 patients with relapsed or refractory indolent B-NHL(either FL,MCL or marginal zone lymphoma).At the ASH 2023 meeting,updates were provided from the B-cell NHL/CLL cohorts.As

244、 of the data cut-off date of September 13,2023,23 r/r B-NHL and 5 B-CLL patients had receivedtreatment with obe-cel.Obe-cel continues to display a favorable tolerability profile with no ICANS or Grade 3 or higher CRS across different indications.Of 28 patients with NHL/CLL evaluable forefficacy,the

245、best ORR was 26/28(92%).Obe-cel was observed to be well-tolerated and active in DLBCL,8/9 evaluable patients entered CMR;6 patients are in ongoing CMR with one relapse at 12months and one unrelated death.In CLL,four of the five treated patients achieved undetectable minimal residual disease(“uMRD”)i

246、n the bone marrow,with all ongoing at the last follow-up date.We continue to evaluate obe-cels potential to address current unmet medical needs in these indications.18Table of contentsUCL has also initiated a Phase 1 exploratory trial(CAROUSEL)of obe-cel in patients with relapsed or refractory PCNSL

247、.CAROUSEL is evaluating the feasibility of generating obe-celand safety of administration in this patient population.UCL presented initial data at the EHA meeting in June 2022.Expansion of obe-cel was observed in the peripheral blood by qPCR,withpersistence in all treated patients at last follow-up.

248、No Grade 3 or greater CRS was observed using intravenous(“IV”)or intra-ventricular obe-cel administration.Two cases of Grade 3 ICANS werereported following IV infusion,whereby the first patient had several neurological deficits that evolved despite ICANS treatment and were compatible with progressiv

249、e PCNSL,as confirmed with themonth 1 MRI scan,and the second patient had neurological deficits that improved with steroids/anakinra.We observed encouraging response rates in six patients evaluable for efficacy following IVadministration of obe-cel.The ORR was four out of six patients(67%),with 2 CRs

250、 and 2 PRs.These four responding patients are without disease progression at the last follow up date.Two patientsdied from progressive PCNSL while part of the study.We expect to report longer follow-up from this trial and enrollment of additional patients is ongoing.Obe-cel for Lupus and Other Autoi

251、mmune DiseasesIn addition to advancing AUCATZYL/obe-cel for oncology indications,we are advancing obe-cel for the treatment of Lupus and other autoimmune diseases.We have initiated the Phase 1CARLYSLE trial to determine the safety,tolerability,and preliminary efficacy of obe-cel in patients with sev

252、ere,refractory systemic lupus erythematosus.Background of SLESystemic lupus erythematosus(“SLE”)is an autoimmune disease characterized by the formation of autoantibodies and immune complexmediated inflammation and organ damage,including the skin,joints,central nervous system,heart,lung,and kidneys.D

253、isease severity changes over time with periods of no disease activity alternated by periods with disease flares/relapses.Insome cases SLE can be life threatening.The disease onset is generally between the ages of 20 and 40,and it affects predominantly young women.The estimated prevalent population o

254、f SLE patientsin the United States,United Kingdom,Germany,France Spain,Italy and Japan is approximately 550,000 patients 60%(330,000 patients)with moderate to severe disease.15%will be refractory tostandard therapies;potentially addressable by CAR T therapy.Currently available treatments are not cur

255、ative and are associated with certain safety concerns.Many patients require life-long immunosuppression,often with high-dose corticosteroids,cyclophosphamide,or mycophenolate mofetil,non-specifically targeting the immune system to reduce inflammation.This results in low-level disease activity in onl

256、y 2544%of patients in the longterm,while sustained complete remission is rare.Approximately 10%of patients with lupus nephritis(“LN”),a form of the disease associated with kidney organ damage,develop end-stage renaldisease in 5 years.Side effects of the current treatment strategies include infection

257、s in the short term and risk for malignancy and cardiovascular disease in the long term,contributing to the reducedlife expectancy of patients with SLE.This substantiates the need for developing better strategies to treat SLE.Autoreactive B cells with autoantibody formation play a key role in the pa

258、thogenesis of SLE.However,B cell depleting agents,such as the anti-CD20 antibody rituximab,did not improveclinical outcomes compared to placebo in randomized studies in SLE and LN while two different biologics have recently been approved in SLE:1.Belimumab,an anti-BAFF/BLyS monoclonal antibody,has b

259、een approved as add-on therapy in adult patients with active,autoantibody-positive SLE with a high degree of disease activitydespite standard therapy.2.Anifrolumab,a type I interferon(“IFN”)receptor antagonist,has also been approved in the United States and EU and is indicated as an add-on for the t

260、reatment of adult patients withmoderate to severe SLE who are receiving standard therapy.Despite these approvals,some patients have insufficient response,lack of response,or lack of sustained response and are at risk for further organ damage despite standard therapy.Hence,challenges remain with trea

261、tment-resistant disease.Another strategy to induce deeper depletion of the B cell compartment originates from the highly effective treatment of patients with B cell malignancies using CD19 CAR T cells.A clinicalstudy by Mackensen and colleagues published in 2023 showed a deep depletion of CD19+B cel

262、ls and plasma blasts in SLE-affected tissues could trigger an immune reset that could allow thecessation of immunosuppressive treatment in patients with SLE.In this study,autologous T cells from 8 patients with SLE were transduced with a lentiviral anti-CD19 CAR vector,expanded andreinfused at a dos

263、e of 110 x6 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide.CAR T cells expanded in vivo and led to deepdepletion of B cells with improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-

264、ds DNA antibodies.Remission of SLE according to standardcriteria was achieved in all patients after 3 months,and drug-free remission was maintained during longer follow-up after CAR T cell administration.19Table of contentsBased on the important role of B cells in the SLE disease pathogenesis and th

265、e preliminary evidence of safety and activity of CD19 CAR T cell therapy in this disease,we have hypothesizedthat treatment with a single infusion of obe-cel may have the potential to eliminate the malfunctioning autoreactive B cells and ameliorate disease in SLE patients in a similar fashion.We bel

266、ieve obe-cels potential advantages over other autoimmune therapies that are approved or in development include its differentiated mechanism of action via its fast-off rate CD19 binder,the existing clinicaldata and approval in r/r B-ALL and our established manufacturing and commercial capabilities.In

267、 particular,the favorable safety profile,with low rates of high-grade CRS and ICANS in the cancersetting,have the potential to drive acceptability of a cell therapy approach in the rheumatology setting.Additionally,the fast-off rate kinetics observed with obe-cel in the cancer setting showincreased

268、T-cell engraftment and profound B-cell depletion.These properties have the potential to drive a deeper cut into CD19+B cells and plasma blasts in SLE-affected tissues,and couldpotentially trigger an immune reset in patients.Obe-cel is the only autologous CD19 CAR T-cell therapy being developed for l

269、upus with an approval in another indication.We expect that datasupporting the safety and manufacture of obe-cel in r/r B-ALL could potentially be useful to support the development of obe-cel in autoimmune indications.Finally,our established commercialsystems and manufacturing infrastructure for AUCA

270、TZYL/obe-cel could be leveraged to support an autoimmune indication.Clinical Development in SLE,LN and other Autoimmune DiseasesThe CARLYSLE trial is a single-arm,open-label,Phase 1 trial to determine the safety,tolerability,and preliminary efficacy of obe-cel in patients with severe,refractory SLE.

271、The primarygoal of this trial is to confirm the fixed dose of obe-cel in adult SLE patients.Six patients received a target dose of 50 x 106 CD19 CAR-positive T cells.Beyond this initial cohort,the study has theoption to add further cohorts of patients.The first CARLYSLE trial was initiated in early

272、2024 and we completed patient doing in early 2025.We expect to provide initial data at our R&D InvestorEvent in April 2025 and follow up presentation of full data at a medical conference in the second half of 2025.Depending on the outcome of the dose confirmation study in SLE,we would plan to initia

273、te further studies in SLE and LN.Furthermore,additional evidence of CD19 CAR T cell treatmentin other autoimmune diseases has been shown by others,including efficacy in patients with idiopathic inflammatory myositis,systemic sclerosis,myasthenia gravis and multiple sclerosis.Dependingon the outcome

274、of the dose confirmation study in SLE,we would plan to investigate obe-cel in additional autoimmune disease indications.AUTO1/22 Our Programmed T Cell Therapy for the Treatment of ALL,other B-cell malignanciesIntroduction to AUTO1/22AUTO1/22 is a dual-targeting CAR T which builds on the obe-cel appr

275、oach utilizing the same CD19 CAR,alongside a novel CD22 CAR designed to reduce antigen negative relapse ofdisease.Antigen negative relapse is a common cause of relapse in patients with pediatric ALL.AUTO1/22 Phase 1 Clinical Trial in Pediatric ALL(CARPALL Trial)We commenced a Phase 1 clinical trial

276、in pediatric patients with relapsed or refractory ALL with our next-generation product candidate,AUTO1/22 in the fourth quarter of 2020.In apublication in Blood in October 2023,we presented data demonstrating a high level of activity,with 83%of patients(10 of 12 patients evaluated)experiencing MRD n

277、egative complete remissions,and a favorable tolerability profile in a very challenging patient population.Patients on study were high risk,with 4 patients who had failed prior CD19 CAR therapy,3 patients with a CD19-negativedisease component,3 patients with non-CNS EMD and 6 patients who had receive

278、d prior blinatumomab.Of 10 responding patients,5 had emergence of MRD(2)or frank relapse(3)with CD19 and CD22 expressing disease associated with loss of CAR T-cell persistence.Importantly,there wereno cases of relapse due to antigen-negative escape,with a median follow-up of 8.7 months.Overall survi

279、val was 75%at 6 and 12 months.Six and 12-month event free survival(EFS)were 75%and60%respectively.This study is no longer enrolling patients.AUTO4:Our T Cell Lymphoma ProgramIntroduction to AUTO4We are developing a programmed T cell product candidate,AUTO4,as a potential treatment for T-cell lymphom

280、as.We are developing this product candidate with a unique targetingapproach that is designed to avoid the severe immunosuppression typically associated with the current investigational CAR T-cell therapies which uses a pan t-cell antigen.for this disease.20Table of contentsT cells have one of two fu

281、nctionally identical genes,known as TRBC1 and TRBC2.A normal/healthy T cell population contains a mix of cells expressing either TRBC1 or TRBC2.Bothforms are active and provide the body with natural immunity,including antiviral immunity.Because T-cell lymphomas are clonal tumors that develop from a

282、single T cell,they are either entirelyTRBC1-positive or entirely TRBC2-positive.Currently available products for the treatment of T-cell lymphoma indiscriminately target all T cells,leading to the severe immunosuppression associatedwith these treatments.We have designed AUTO4 as a programmed T cell

283、to specifically target and deplete cells expressing TRBC1,while preserving healthy T cells that express TRBC2.A normal T cellpopulation consists of varying amounts of TRBC1-positive and TRBC2-positive T cells.Based on the typical distribution of TRBC1-positive and TRBC2-positive T cells,we believe t

284、hat patientstreated with AUTO4 should be left with a population of healthy,functional polyclonal T cells,which provides the immune system of these patients the ability to respond to bacterial and viralinfections and other pathogens.In addition,this product candidate will have a built-in safety switc

285、h designed to eliminate the programmed CAR T cells in the event a patient suffers certain seriousadverse events related to the CAR T cell therapy,such as CRS or neurotoxicity.Background of T Cell LymphomaMature T cell lymphomas are aggressive,treatment resistant malignancies that are associated with

286、 poor prognosis.Clinical application of immunotherapeutic approaches has been limited bya lack of target antigens that discriminate malignant from healthy/polyclonal T cells.T cell lymphoma is a rare and heterogeneous form of NHL,representing approximately 10 to 20%of NHL casesand 3 to 4%of all hema

287、tological malignancies.Most T cell lymphomas are peripheral T cell lymphomas,(PTCL),the initial indication for which we are developing AUTO4.PTCL generallyinvolves high-grade tumors and occurs at a similar age as aggressive B cell lymphomas,with a relatively high proportion of patients becoming rapi

288、dly unwell.For the majority the PTCL subtypes,the five-year survival rate may range from 18%to 24%.The three most common subtypes of PTCL are peripheral T cell lymphoma not otherwise specified(“PTCL-NOS”),anaplastic large-celllymphoma(“ALCL”),and angioimmunoblastic T cell lymphoma(“AITL”),together a

289、ccounting for approximately 70%of all PTCLs in the United States.The first-line treatment for PTCL consists of the combination chemotherapy(e.g.CHOP,consisting of cyclophosphamide,vincristine,doxorubicin and prednisolone).However,with CHOPchemotherapy,CR rates are low and disease relapse is common.I

290、n many treatment centers,CHOP chemotherapy may be consolidated with autologous or allogenic stem cell transplantation inselected patients.Little is understood in terms of treatment guidance for the other PTCL subtypes and these lymphomas lack clear treatment guidelines.A large proportion of T cell l

291、ymphoma patients arerefractory to or relapse following treatment with standard therapies and there remains a need to develop an effective therapy for this currently unmet medical need.Unlike B cell lymphomas,T cell lymphomas have not benefited from advances in immunotherapeutic approaches.This is ma

292、inly due to the lack of therapeutic development in T celllymphomas to identify suitable target antigens to distinguish malignant T cells from normal/polyclonal T cells.While a similar problem exists with B cell lymphomas,targeting a pan B cell antigen isan acceptable strategy,as the concomitant depl

293、etion of the normal B cell compartment is well tolerated,and some targeted approaches may be ameliorated by the administration of immunoglobulin.In contrast,targeting a pan T cell antigen would result in severe immunosuppression,where there is currently no available rescue medication.Some competitor

294、s that are pursuing this approach areplanning to use CAR T cells therapy as a bridging to SCT.However,this approach would only benefit the transplant eligible patients who may not be the majority of the T cell lymphoma patients.There is currently no programmed T cell therapy that is being developed

295、as a standalone treatment.Clinical Development of AUTO4In the fourth quarter of 2018,we began enrolling patients in a single-arm,open label,multi-center Phase 1/2 clinical trial,Libra T1,in patients with TRBC1 positive PTCL-NOS,AITL andALCL,the three most common subtypes of PTCL,for which patients h

296、ave failed,or have relapsed disease following,at least one prior therapy.We refer to this trial as the LibrA-T1 trial,which wasinitiated at sites in the U.K.and Spain in 2018 and 2020 respectively.Patients were screened for TRBC status of tumor cells using a CE-marked next-generation sequencing(“NGS

297、”)method prior tofull enrollment in the trial.The main objective of the Phase 1 portion of the trial was to evaluate the safety of AUTO4 and to determine a recommended dose for the Phase 2 portion of the trial.The main objective ofthe Phase 2 portion will be to further evaluate the safety of the tre

298、atment and evaluate efficacy endpoints,such as ORR and CR rate.We designed the trial to evaluate up to five dose levels of AUTO4,beginning with a low dose of 25 million AUTO4 cells.If we do not observe any dose limiting toxicities(“DLT”),the doseescalation phase of the trial will continue to higher

299、doses of 75 million AUTO4 cells,225 million AUTO4 cells,450 million and potentially 900 million AUTO4 cells.21Table of contentsData from the first 13 patients dosed in the Libra T1 trial was presented at the ICML in June 2023.At the cutoff date of April 28,2023,19 patients were enrolled into the stu

300、dy and 13 weredosed.Using manufacturing process A,10 patients were dosed.Using manufacturing process B,3 additional patients were dosed.Among the 13 patients dosed with AUTO4,the treatment was welltolerated with no DLT.Ongoing responses at 15 and 18 months post-dosing at the highest dose tested(450

301、x106)are encouraging.Presence of CAR T cells in the lymph nodes of patients suggest fasthoming of CAR T cells to the tumor site,despite absence in the blood.Efficacy data from Process B was not provided given median follow up is 12 months.No cases of ICANS or CRS Gr3 were observed across all subject

302、s during the period.While persistence data from the dual targeting cohort is immature,it demonstrates expansion of three CAR populations and suggests a trend toincreased persistence of D8 BCMA CAR expressing T cells.The study is ongoing and continues to recruit patients.22Table of contentsOur Solid

303、Tumor ProgramsSolid tumors present a particular challenge to CAR T cell therapies,since solid tumors tend to fend off T cells with upregulation of checkpoint inhibition and a hostile microenvironment.Inaddition,contrary to hematological cancer cells that are readily accessible to programmed T cells

304、in the circulating blood of a patient,solid tumors are more difficult for programmed T cells to trackdown in sufficient numbers to impact the disease.In addition,the persistence of programmed T cells tends to be limited,which also leads to a reduced effect on solid tumor cells.In addition to theprog

305、rams we are currently pursuing described below,we intend to continue to evaluate other possible solid tumor indications.AUTO6:Our Neuroblastoma ProgramIntroduction to AUTO6 and AUTO6NGUnder our license agreement with University College of London Business Ltd.(“UCLB”),we have been granted an exclusiv

306、e,worldwide license to AUTO6(1RG-CART),a programmed Tcell product candidate targeting the glycosphingolipid GD2.Cancer Research UK(“CRUK”)has completed an exploratory Phase 1 clinical trial of AUTO6 in pediatric patients with neuroblastoma.We are developing a next-generation product candidate,which

307、we refer to as AUTO6NG,incorporating additional programming modules designed to improve efficacy,safety and persistence ofAUTO6.Background of NeuroblastomaNeuroblastoma is a cancer that develops from immature nerve cells found in several areas of the body,and most commonly arises in and around the a

308、drenal glands,which have similarorigins to nerve cells and sit atop the kidneys.However,neuroblastoma can also develop in other areas of the abdomen and in the chest,neck and near the spine,where groups of nerve cells exist.Neuroblastoma most commonly affects children age five or younger,though it m

309、ay rarely occur in older children.According to the American Cancer Society,there are approximately 700 to 800 newcases of neuroblastoma each year in the United States.Preclinical Studies of AUTO6/6NGIn preclinical in vitro studies,AUTO6 selectively,effectively and efficiently killed GD2-expressing t

310、umor cells while sparing cells that did not express GD2.In addition,the RQR8 safetyswitch activation by rituximab was tested in vitro,where the addition of rituximab was shown to activate the safety switch and eliminate the programmed T cells from the culture,and residual cellsdid not possess any in

311、trinsic anti-GD2 activity.This safety switch activation was also observed in vivo in a mouse model,where the murine analogue of rituximab was able to deplete the GD2-targeting programmed T cell product candidate from the bone marrow,blood,lymph node and spleen of animals that had previously been eng

312、rafted with programmed T cells.In 2016,in collaboration with Cancer Research UKs Centre for Drug Development we initiated a single-arm Phase 1 dose escalation trial of AUTO6 in relapsed or refractory neuroblastomaat two pediatric cancer centers in the U.K.The trial evaluated the safety and efficacy

313、of AUTO6.In 2020 the data from the AUTO6 Phase 1 clinical trial was published in Science TranslationalMedicine.The results from the study showed that AUTO6 can induce rapid regression of bulky disease in a solid tumor setting without inducing on-target,off-tumor toxicity,despite dose dependentCAR T

314、expansion.CAR T cell expansion was observed in all 6 patients treated at the higher cell dose cohorts in this Phase 1 study.Three of these six patients demonstrated evidence of transientCAR T cell activity,including CRS,and regression of soft tissue and BM disease activity.The GD2 binder used in AUT

315、O6 has been designed to minimize on-target,off-tumor neurotoxicity associated with GD2 expression at low levels in pain fibers and the brain.Despite thepresence of clear CAR T cell activity,no neurotoxicity was observed.The publication also suggests that,whilst AUTO6 is a valid and safe strategy for

316、 targeting neuroblastoma,further modificationsare required to promote CAR T cell persistence and induce deeper and more durable responses for these patients.In November 2019,we reported preclinical data of AUTO6NG.Building on AUTO6,in AUTO6NG we introduced additional programming modules in order to

317、help the programmed T cellspersist in and withstand the hostile tumor microenvironment.AUTO6NG is a programmed T cell therapy incorporating the GD2-targeted CAR T and RQR8 safety switch from AUTO6 but alsoincorporating three additional programming modules:(i)an IL7 CCR designed to increase persisten

318、ce,(ii)a dominant negative TGFbRII protein designed to block inhibitor signals from TGFb and(iii)a truncated SHP2 protein designed to block inhibitor signals from PD1.These modules are delivered,or transduced,into the T cells via two viral vectors.Both single-and dual-transduced CART cells were eval

319、uated in vitro for anti-tumor activity,cytokine secretion,T cell proliferation,survival,and resistance to immunosuppressive pathways.The addition of these three modules in the AUTO6NG product candidate significantly augmented its function by extending T cell persistence and rendering modified T cell

320、s resistant toTGFb-and PD1/PDL1-driven immune inhibition when compared to AUTO6 in vitro.Additionally,intravenous delivery of AUTO6NG in mice with established tumor burden exhibited potent anti-tumor activity and extended survival,whereas AUTO6 showed no activity in that model.23Table of contentsWe

321、presented new preclinical data for AUTO6NG in June 2020 at the American Association for Cancer Research(“AACR”)Virtual Annual Meeting 2020.GD2 was evaluated as atherapeutic CAR T target antigen in SCLC.We observed that AUTO6 alone has demonstrated efficacy in an in vitro SCLC model;however,successfu

322、l tumor targeting alone was not sufficient todrive meaningful in vivo efficacy in the same SCLC model.We presented new preclinical data demonstrating the ability to target GD2 in SCLC cell line models in vitro,and the requirement forenhancing modules,designed to overcome TME suppressive mechanisms,t

323、o drive superior in vivo efficacy in a SCLC mouse model.The data suggests that AUTO6NG can overcome the immunesuppressive mechanisms in the TME.Clinical Development Strategy of AUTO6NGGD2 is expressed in numerous pediatric and adult tumors including neuroblastoma,osteosarcoma,soft tissue sarcoma,mel

324、anoma,astrocytoma and small cell lung cancer(“SCLC”).A Phase1 clinical trial of AUTO6NG in r/r neuroblastoma was initiated in December 2023 in collaboration with UCL.This study is currently enrolling patientsCommercialization and Manufacturing Plans for our Clinical-Stage ProgramsWe are developing o

325、ur clinical-stage programs for the treatment of patients with late-stage or rare hematological cancers and solid tumors,most of whom are treated in specialized treatmentcenters or hospitals.With our experience in gene therapy,transplantation and oncology,we aim to provide high levels of service and

326、scientific engagement at these treatment centers,and to pilot andestablish systems necessary for product delivery by the time of launch.By focusing on these centers,we can begin to build our commercialization capabilities with limited resources.We are alsoplanning to advance obe-cel in autoimmune in

327、dications,and plan to leverage our established clinical and commercial manufacturing infrastructure,including our purpose-built manufacturing facility,the Nucleus.We have retained worldwide commercial rights for our product candidates.We plan to expand our global commercialization capabilities over

328、time such that we are able to commercialize anyproduct candidate in a broader number of countries over time,but with a focus on achieving an early presence in the U.S.,U.K.and parts of Europe,i.e.countries where we expect to obtain aregulatory approval.We may pursue strategic collaborations with thi

329、rd parties in order to maximize the commercial potential of our product candidates.Under the terms of the License and OptionAgreement with BioNTech,BioNTech has certain options to co-promote or co-commercialize AUTO1/22 and AUTO6NG.We generally expect to launch any of our products that receive regul

330、atoryapproval in the United States first,followed by the U.K.,EU and subsequently in other major markets.The product option for AUTO1/22 was not exercised as of February 8,2025 and has expired.See“Risk FactorsRisks Related to our Intellectual PropertyThird parties may initiate legal proceedings alle

331、ging that we are infringing their intellectual property rights,the outcome of which wouldbe uncertain and could significantly harm our business.”In addition to the Nucleus,we maintain separate manufacturing capabilities for clinical-stage programs separate to The Nucleus(which is used exclusively fo

332、r commercial manufacturing ofAUCATZYL)to support further clinical trials of obe-cel in autoimmune conditions and potentially future hematological indications.For clinical trial supply,we have established our internal cell andvector manufacturing capacity at the Cell and Gene Therapy Catapult in Stev

333、enage,United Kingdom.We have a cell manufacturing suite capable of supporting clinical supply operations.Our early-stage programs such as AUTO1/22 and AUTO6NG are manufactured in collaboration with the UCL study teams.However,phase-appropriate Process Development activities havebeen initiated within our laboratories in order to leverage our existing manufacturing capabilities for progression to a