Merus (MRUS) 2022年年度報告「NASDAQ」.pdf

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1、 UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington,D.C.20549 FORM 10-K (Mark One)c ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2022OR TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT

2、 OF 1934 For the transition period from toCommission File Number 001-37773 MERUS N.V.(Exact name of Registrant as specified in its Charter)The NetherlandsNot Applicable(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)Uppsalalaan 173584 CT UtrechtThe Neth

3、erlandsNot Applicable(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:+31 30 253 8800 Securities registered pursuant to Section 12(b)of the Act:Title of each class TradingSymbol(s)Name of each exchange on which registeredCommon shares,nominal value 0

4、.09 per share MRUS The Nasdaq Stock Market LLC(Nasdaq Global Market)Securities 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 n

5、ot required to file reports pursuant to Section 13 or 15(d)of the Act.YES NO Indicate 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 such shorter period that the Reg

6、istrant 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(232.405 of

7、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 grow

8、th company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filer Accelerated filer Non-accelerated filer Smaller reporting company Emerging growth company If an emerging gr

9、owth 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 standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on a

10、nd attestation to its managements assessment of the effectiveness of its internal control over financial reporting under Section 404(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

11、Section 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 to previously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recover

12、y analysis of incentive-based compensation received by any of the registrants executive officers during 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 Exchange Act).YES NO The aggregate market val

13、ue of the voting and non-voting common equity held by non-affiliates of the registrant,based on the closing price of the shares of common stock on The Nasdaq Stock Market on June 30,2022,was approximately$1,033.5 million.The number of shares of registrants Common Shares outstanding as of February 22

14、,2023 was 46,317,281.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants definitive proxy statement that the registrant intends to file with the Securities and Exchange Commission pursuant to Regulation 14A in connection with the registrants 2023 Annual General Meeting of Shareholders are

15、 incorporated by reference into Part III of this Annual Report on Form 10-K to the extent stated herein.Auditor Firm Id 1012 Auditor Name:KPMG Accountants N.V.Auditor Location:Rotterdam,The Netherlands Table of Contents PagePART I Item 1.Business 3Item 1A.Risk Factors 44Item 1B.Unresolved Staff Comm

16、ents 87Item 2.Properties 87Item 3.Legal Proceedings 88Item 4.Mine Safety Disclosures 88 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities 89Item 6.Reserved 89Item 7.Managements Discussion and Analysis of Financial Condition and

17、Results of Operations 90Item 7A.Quantitative and Qualitative Disclosures About Market Risk 99Item 8.Financial Statements and Supplementary Data 99Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure 99Item 9A.Controls and Procedures 99Item 9B.Other Information

18、100Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 100 PART III Item 10.Directors,Executive Officers and Corporate Governance 101Item 11.Executive Compensation 103Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 104Ite

19、m 13.Certain Relationships and Related Transactions,and Director Independence 104Item 14.Principal Accounting Fees and Services 104 PART IV Item 15.Exhibits,Financial Statement Schedules 105Item 16Form 10-K Summary 108 i CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS This Annual Report on Form

20、 10-K contains forward-looking statements.All statements other than statements of historical facts contained in this Annual Report on Form 10-K are forward-looking statements.In some cases,you can identify forward-looking statements by terms such as“may,”“will,”“should,”“expect,”“plan,”“anticipate,”

21、“could,”“intend,”“target,”“project,”“contemplate,”“believe,”“estimate,”“forecast,”“predict,”“potential”or“continue”or the negative of these terms or other similar expressions,although not all forward-looking statements contain these words.Forward-looking statements contained in this Annual Report on

22、 Form 10-K,include without limitation statements regarding our plans to develop and commercialize our product candidates,the timing of our ongoing or planned clinical trials,the timing of and our ability to obtain and maintain regulatory approvals,the clinical utility of our product candidates,our c

23、ommercialization,marketing and manufacturing capabilities and strategy,our expectations surrounding our collaborations,our expectations about the willingness of healthcare professionals to use our product candidates,the sufficiency of our cash,cash equivalents and investments,and the plans and objec

24、tives of management for future operations and capital expenditures.The forward-looking statements in this Annual Report on Form 10-K are only predictions and are based largely on our current expectations and projections about future events and financial trends that we believe may affect our business

25、,financial condition and results of operations.These forward-looking statements speak only as of the date of this Annual Report on Form 10-K and are subject to a number of known and unknown risks,uncertainties and assumptions and other important factors,including those described under the sections i

26、n this Annual Report on Form 10-K entitled“Summary Risk Factors,”“Risk Factors”and“Managements Discussion and Analysis of Financial Condition and Results of Operations”and elsewhere in this Annual Report on Form 10-K.Because forward-looking statements are inherently subject to risks and uncertaintie

27、s,some of which cannot be predicted or quantified and some of which are beyond our control,you should not rely on these forward-looking statements as predictions of future events.The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results

28、could differ materially from those projected in the forward-looking statements.Moreover,we operate in an evolving environment.New risk factors and uncertainties may emerge from time to time,and it is not possible for management to predict all risk factors and uncertainties.Except as required by appl

29、icable law,we do not plan to publicly update or revise any forward-looking statements contained herein,whether as a result of any new information,future events,changed circumstances or otherwise.We intend the forward-looking statements contained in this Annual Report on Form 10-K to be covered by th

30、e safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act of 1933,as amended,or the Securities Act,and Section 21E of the Securities Exchange Act of 1934,as amended,or the Exchange Act.SUMMARY RISK FACTORSOur business is subject to numerous risks and unce

31、rtainties,including those described in Part I,Item 1A.“Risk Factors”in this Annual Report on Form 10-K.You should carefully consider these risks and uncertainties when investing in our common shares.The principal risks and uncertainties affecting our business include the following:We have incurred s

32、ignificant net losses since our inception and we expect to continue to incur significant expenses and operating losses for the foreseeable future.We have a limited operating history,have not completed any registrational clinical trials,and have no products approved for commercial sale,which may make

33、 it difficult for you to evaluate our current business and predict our future success and viability.We will require substantial additional capital to finance our operations.If we are unable to raise such capital when needed,or on acceptable terms,we may be forced to delay,reduce or eliminate one or

34、more of our research and drug development programs or future commercialization efforts.The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials,and the results of our clinical trials may not satisfy the requirements of the FDA,EMA or

35、other comparable foreign regulatory authorities.The clinical trial and regulatory approval processes are lengthy,time consuming and inherently unpredictable,and we may incur additional costs or experience delays in completing,or ultimately be unable to complete,the development and commercialization

36、of our product candidates.Our antibody candidates may have serious adverse,undesirable or unacceptable side effects which may delay or prevent marketing approval.If such side effects are identified during the development of our antibody candidates or following approval,if any,we may need to abandon

37、our development of such antibody candidates,the commercial profile of any 1 approved label may be limited,or we may be subject to other significant negative consequences following marketing approval,if any.We have never commercialized an antibody candidate before and may lack the necessary expertise

38、,personnel and resources to successfully commercialize our products on our own or together with suitable collaborators.We rely,and expect to continue to rely,on third parties,including independent clinical investigators and contract research organizations or CROs,to conduct our pre-clinical studies,

39、clinical trials,chemistry,manufacturing and controls and potential development of a companion diagnostic.If these third parties do not successfully carry out their contractual duties,meet expected deadlines or perform at reasonable cost,we may not be able to obtain regulatory approval for or commerc

40、ialize our antibody candidates or we may be subject to other significant negative consequences following marketing approval,if any,and our business could be substantially harmed.Due to our limited resources and access to capital,we must,and have in the past decided to,prioritize development of certa

41、in antibody candidates over other potential candidates.These decisions may prove to have been wrong and may adversely affect our revenues.The competition for qualified personnel is particularly intense in our industry.If we are unable to retain or hire key personnel,we may not be able to sustain or

42、grow our business.We operate in highly competitive and rapidly changing industries,and if our competitors develop and market technologies or products more rapidly than we do or that are more effective,safer or less expensive than the product candidates we develop,our commercial opportunities will be

43、 negatively impacted.Our success depends on our ability to protect our intellectual property and our proprietary technologies.If we are unable to adequately protect our intellectual property and our proprietary technologies or obtain and maintain issued patents which are sufficient to protect our pr

44、oduct candidates and proprietary technologies,or if others do not respect our intellectual property rights and exclusivity,others could compete against us more directly,which would negatively impact our business.Our existing collaboration agreements are important to our business and potential future

45、 collaborations and licenses may also be important to us,and if we are unable to maintain any of these collaborations or execute new collaborations or licenses,or if these arrangements are not successful,our business could be adversely affected.The trading prices for our and other biopharmaceutical

46、companies stock have been highly volatile as a result of disruptions and extreme volatility in the global economy,including rising inflation and interest rates,declines in economic growth,the conflict between Russia and Ukraine and the COVID-19 pandemic,which have and may continue to adversely impac

47、t our business,including our pre-clinical studies and clinical trials,financial condition,our ability to raise capital and results of operations.2 PART IItem 1.Business.Overview We are a clinical-stage oncology company developing innovative antibody therapeutics.Our pipeline of full-length,human,mul

48、tispecific antibody candidates is generated from our proprietary technology platforms,which are able to generate a diverse array of antibody binding domains,or Fabs,against virtually any target.Each antibody binding domain consists of a target-specific heavy chain paired with a common light chain.Mu

49、ltiple binding domains can be combined to produce novel multispecific antibodies that bind to a wide range of targets and display novel and innovative biology.These platforms,referred to as Biclonics and Triclonics,allow us to generate large numbers of diverse panels of bispecific and trispecific an

50、tibodies,respectively,which can then be functionally screened in large-scale cell-based assays to identify those unique molecules that possess novel biology,which we believe are best suited for a given therapeutic application.Further,by binding to multiple targets,Biclonics and Triclonics may be des

51、igned to provide a variety of mechanisms of action,including simultaneously blocking receptors that drive tumor cell growth and survival and mobilizing the patients immune response by engaging T cells,and/or activating various killer cells to eradicate tumors.Our technology platforms employ an assor

52、tment of patented technologies and techniques to generate human antibodies.We utilize our patented MeMo mouse to produce a host of antibodies with diverse heavy chains and a common light chain that are capable of binding to virtually any antigen target.We use our patented heavy chain and CH3 domain

53、dimerization technology to generate substantially pure bispecific and trispecific antibodies.We also employ our patented Spleen to Screen technology to efficiently screen panels of diverse heavy chains,designed to allow us to more rapidly identify Biclonics and Triclonics therapeutic candidates with

54、 differentiated modes of action for pre-clinical and clinical testing.Using our Biclonics platform we have produced,and are currently developing,the following candidates:MCLA-128(zenocutuzumab or Zeno)for the potential treatment of solid tumors that harbor Neuregulin 1(NRG1)gene fusions and Zeno in

55、combination with an androgen deprivation therapy for the potential treatment of castration resistant prostate cancer(CRPC);MCLA-158(petosemtamab)for the potential treatment of solid tumors;MCLA-129,for the potential treatment of lung and other solid tumors;and MCLA-145 for the potential treatment of

56、 solid tumors.Furthermore,we have a pipeline of proprietary antibody candidates in pre-clinical development and intend to further leverage our Biclonics and Triclonics technology platforms to identify multiple additional antibody candidates and advance them to clinical development.Our Strategy Our g

57、oal is to become a leading oncology company developing innovative multispecific antibodies to treat various types of cancer.Our business strategy comprises the following components:Successfully develop our most advanced bispecific antibody candidate,zenocutuzumab,for the treatment of NRG1 fusion sol

58、id tumors,and explore other potential indications in non-NRG1 fusion cancers by targeting both HER2 and HER3.We are developing our most advanced bispecific antibody candidate,zenocutuzumab,for the potential treatment of solid tumors that contain NRG1 gene fusions.The NRG1 protein is the ligand for t

59、he HER3 receptora known cause of cancer cell growth.The gene encoding NRG1 can form genetic rearrangements referred to as NRG1 gene fusions.The protein product of the NRG1 gene fusion can drive signaling through the HER3 receptor and thus drive cancer cell growth.NRG1 gene fusions(NRG1+)occur infreq

60、uently in a wide range of different cancer types.Zenocutuzumab has been shown pre-clinically to potently disrupt binding of NRG1(and NRG1-fusion proteins)to HER3 and halt NRG1-stimulated tumor cell growth.In July 2020,the FDA granted zenocutuzumab orphan drug designation for the treatment of patient

61、s with pancreatic cancer and in January 2021,the FDA granted Fast Track Designation to zenocutuzumab for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions that have progressed on standard-of-care therapy.We plan to provide an update on the potential registrational pa

62、th and timeline in NRG1+cancer in the first half of 2023 and a clinical update on zenocutuzumab in NRG1+cancer at a major medical conference in 2023.Further,we are evaluating a cohort exploring the combination of zenocutuzumab with enzalutamide or abiraterone,an androgen deprivation therapy(ADT)in c

63、astration resistant prostate cancer(CRPC),and we plan to provide an initial clinical data update on zenocutuzumab in CRPC in the second half of 2023.Further,we are evaluating a cohort exploring the combination of zenocutuzumab and afatinib for patients with NRG1+non-small cell lung cancer(NSCLC).3 S

64、uccessfully develop our bispecific antibody candidate MCLA-158,petosemtamab.We are developing petosemtamab for a potential dual EGFR/LRG5 blockade for the treatment of solid tumors.Our phase 1 clinical trial of petosemtamab is ongoing in the dose expansion phase.In October 2021,we presented interim

65、clinical data in patients with advanced head and neck squamous cell carcinoma(HNSCC)at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics.As of the safety and efficacy data cutoff date of August 9,2021,10 patients with advanced HNSCC were enrolled and se

66、ven were evaluable for an interim efficacy analysis by investigator assessment.Three of seven patients achieved partial responses,with one of these three achieving complete response after the data cutoff date.Tumor reduction was observed in all seven patients.Enrollment of patients continues at this

67、 dose in the expansion phase of the open-label,multicenter trial.We plan to provide a clinical update in the first half of 2023 at a medical conference and plan to provide a regulatory path update in the first half of 2023.Successfully develop our bispecific antibody candidate MCLA-129.We are develo

68、ping MCLA-129 as a potential treatment for solid tumors,including NSCLC.In May 2021,we announced that the first patient was treated in the phase 1/2 dose escalation and expansion trial evaluating MCLA-129 for the treatment of patients with advanced NSCLC and other solid tumors.The MCLA-129 trial is

69、ongoing in the dose expansion phase,treating patients with MCLA-129 monotherapy in c-MET exon 14 mutant(mt)NSCLC,exon 20 insertion(EGFRex20)NSCLC,HNSCC,as well as in combination with Tagrisso(osimertinib)a third generation EGFR tyrosine kinase inhibitor(TKI)in treatment naive EGFRmt NSCLC and in pat

70、ients with EGFRmt NSCLC that have progressed on Tagrisso.We plan to provide an initial clinical data update from the expansion cohorts,and a further clinical development strategy update in the second half of 2023.MCLA-129 is subject to a collaboration and license agreement between Merus and Betta Ph

71、armaceuticals Co.Ltd.(Betta),whereby Merus exclusively licensed Betta to develop MCLA-129 in China,while Merus retains full ex-China rights.Successfully develop our bispecific antibody candidate MCLA-145.We are developing MCLA-145 in an ongoing phase 1 trial for the potential treatment of solid tumo

72、rs.MCLA-145 is designed to recruit,activate and prevent the exhaustion of tumor-infiltrating T-cells.The trial consists of a dose escalation phase,followed by a planned dose expansion phase.In December 2021,we presented interim clinical data on MCLA-145 from the phase 1 trial dose escalation study i

73、n patients with solid tumors at the ESMO Immuno-Oncology Congress 2021.As of the data cutoff date of July 14,2021,34 patients with advanced or metastatic solid tumors had been treated at eight dose levels ranging from 0.4-75mg every two weeks.Preliminary evidence of antitumor activity was observed a

74、t doses 25 mg biweekly.We have also initiated a cohort combining MCLA-145 with Keytruda(pembrolizumab)a PD-1 blocking antibody,with enrollment on-going.Accelerate the discovery and development of additional internal and collaboration-related bispecific antibody candidates and internal trispecific an

75、tibody candidates.We believe we are well positioned to expand our pipeline of Biclonics and Triclonics molecules for the potential treatment of cancer and potentially other forms of disease.We are conducting pre-clinical studies for our internal proprietary bispecific and trispecific pipeline as wel

76、l as leveraging our bispecific platform with our collaborators including Incyte,Eli Lilly and Company(Eli Lilly)and Betta.Seek strategic collaborations.We intend to seek strategic collaborations to facilitate the capital-efficient development of our pipeline and to maximize the value of our Biclonic

77、s and Triclonics technology platforms and to access unique partner capabilities and capacity.We have entered into collaborations with Incyte,Eli Lilly,and Betta to develop bispecific antibody candidates based on our Biclonics technology platform.We plan to work with other potential future collaborat

78、ors to further validate and expand the use of our Biclonics and Triclonics platforms in developing bispecific and trispecific antibody candidates.We have also worked with Ono Pharmaceutical Co.,Ltd.,under a research license agreement to generate bispecific antibodies,including for indications in and

79、 outside oncology,which further underscore the breadth of the Merus platform.We believe these collaborations,license and future agreements could potentially provide significant funding to advance our pipeline and allow us to benefit from the additional resources,development and commercialization exp

80、ertise of our collaborators.4 Our Biclonics and Triclonics Candidate Portfolio We currently have bispecific candidates in clinical development,with a variety bispecific and trispecific candidates in pre-clinical development.The following table summarizes our development candidate pipeline:Cancer Imm

81、unotherapeutics Immunotherapy is a relatively new class of cancer treatment that works to harness a patients own immune system to attack the cancer cells.There are a number of immunotherapies that are designed to engage various aspects of the immune system,for example:(1)adaptive immunity,specifical

82、ly directing genetically modified T cells to the tumor with chimeric antigen receptor,or CAR T cells or T-cell receptor modification;or modulating T-cell activity through co-stimulation or checkpoint signals;and(2)innate immunity,including antibody-dependent cellular cytotoxicity(ADCC),cellular-depe

83、ndent cytotoxicity(CDC),monocyte/macrophage cytotoxicity,natural killer(NK)cell cytotoxicity,or other forms of T-cell cytotoxicity;all directed at the cancer cells.While these therapies vary in mechanism of action,they rely on specific components of the innate or adaptive immune system to kill tumor

84、 cells or counteract signals produced by cancer cells that suppress immune responses.While these approaches have advanced the field of oncology,each also have limitations.For example,the enhanced ADCC of monoclonal antibodies that bind to a single target expressed by tumor cells can potentially indu

85、ce an autoimmune“on-target,off-tumor”toxicity to normal non-tumor tissues that may also express the same target antigen.Cell-based therapies such as genetically modified CAR-T cells can be difficult and expensive to manufacture,can persist in patients for many months,can be associated with a toxic c

86、ytokine release syndrome as safety concerns,or can become ineffective if the tumor loses expression of the single antigen against which the CAR-T cells are directed.We believe multispecific antibody candidates developed from our novel platforms offer the potential to overcome these limitations.Backg

87、round on Antibodies The conventional antibody in full length immunoglobulin G(IgG)format is a Y-shaped molecule that consists of two identical heavy chains and two identical light chains,as shown in the figure below.Each heavy chain pairs with the light chain to form two variable regions,or antigen

88、binding fragment,Fab,that bind to antigens,or targets,and a constant region,which includes a region known as the fragment crystallizable(Fc)that binds to receptors present on effector cells in the immune system.In conventional full-length IgG,the variable regions are identical and bind to the same t

89、argets.5 In multispecific antibodies,the two or more variable regions bind to two or more different targets.To achieve this in the full-length IgG format,different heavy chain variable regions that can use a common light chain are combined.In addition,modifications of the heavy chain Fc regions are

90、engineered to drive the formation of full-length IgG that use two different heavy chains rather that two copies of the same heavy chain,which make a monospecific antibody.In both conventional monoclonal antibodies(mAbs)and IgG multispecific antibodies,the Fc region can bind to Fc receptors present o

91、n effector cells.This binding results in the recruitment and activation of immune effector cells and amplifies the immune systems response to antigens bound by the variable region of the antibody.This process is called ADCC.The Fc region can be modified to enhance ADCC so as to generate a more poten

92、t immune response against a particular target.The Fc region can also be silenced to block interactions with the immune system.Our Biclonics and Triclonics Platforms Our two technology platforms use large-scale functional screening in molecular and cell-based assays to identify novel,innovative Biclo

93、nics and Triclonics with the specific characteristics desired for further development.We believe our Biclonics and Triclonics platforms allow us to approach cancer treatment through multiple innovative modes of action:Blocking oncogenic growth factor signaling by disrupting the signaling pathways th

94、at drive tumor cell growth or resistance to monoclonal antibody therapy.This includes,for example tumor cell growth driven by NRG1 fusions interacting with the HER3 receptor.Hard-to-target receptors that may drive tumor growth or escape can be targeted by our Dock and Block mechanism whereby the bin

95、ding a tumor associated target prevalent on cancer cells facilitates a second domain to bind and block lesser expressed targets that are critical for cancer growth.Engaging an adaptive immune response by recruiting T-cells and/or modulating co-stimulation or checkpoint inhibition.We can produce mult

96、ispecific antibodies that are designed to simultaneously bind to the T-cell antigen CD3 or other effector cell engaging antigens,and/or tumor-associated targets,for a potentially potent T cell or other effector cell recruitment and engagement to selectively kill tumor cells.Engaging the innate immun

97、e response through multiple mechanisms.We can produce enhanced ADCC modifications in the Fc region of ourBiclonics or Triclonics designed to facilitate the recruitment of immune effector cells,such as natural killer cells,or NK cells,and macrophages,to directly kill tumor cells.Specific binding doma

98、ins engineered in multispecific antibodies can directly bind to macrophages and monocytes;NK cells,each providing specific immune cell function to attack cancer cells.Employing combinations of the above mechanisms.Using our platforms,we can design antibodies to simultaneously target a growth factor

99、receptor expressed by tumor cells and an immunomodulatory molecule involved in blocking and/or reactivating tumor-specific T cells.Biclonics and Triclonics can be designed to target growth factor receptors,like 6 epidermal growth factor receptors(EGFR)and HER2 that are expressed on many tumors,while

100、 delivering an activation signal or checkpoint blockade to T cells.Our process to select lead Biclonics for clinical development is illustrated below.We use our patented MeMo,Spleen to Screen,heterodimerization technology,human antibody generation and Biclonics production technologies to rapidly bui

101、ld large collections of Biclonics or Triclonics directed against particular target combinations.We then test these collections in cell-based functional assays to identify multispecific antibodies that have the potential for novel and innovative modes of action.We select the most potent or efficaciou

102、s and evaluate them in multiple in vitro and in vivo assays to identify lead candidates for clinical development.Selection of Lead Multiclonics Our Biclonics technology platform includes the following:Human antibody generation.Our platform for generating human antibodies employs our patented transge

103、nic common light chain technology,which we refer to as MeMo,which harbors human heavy chain variable regions and a human common light chain in its germline.MeMo harnesses the power of the in vivo immune system to yield human antibodies with the potential for high affinity,specificity,optimal biophys

104、ical characteristics and low immunogenicity.Upon immunization,MeMo is capable of generating large and diverse panels of human common light chain antibodies against a broad variety of targets.These human common light chain antibodies are then used to generate large and diverse panels of human multisp

105、ecific antibodies capable of binding different targets of virtually any combination.Patented dimerization technology and the full-length Immunoglobulin G format.Our Biclonics consist of two different heavy chains that need to stably form,or heterodimerize,inside a manufacturing cell line.Using our p

106、atented dimerization technology,we employ amino acid residues with opposite charges in the CH3 domains of these heavy chains to efficiently drive the formation of the heterodimer bispecific antibody rather than the homodimer antibody consisting of two copies of the same heavy chain.In addition,the u

107、se of a single,or common,light chain in our human Biclonics antibodies ensures that each heavy chain pairs with the correct,common light chain to efficiently form the intended functional antigen binding regions.The combination of these approaches prevents the need for additional,more artificial tech

108、niques,such as the use of linkers or chemical reactions,to force the pairing of different parts of the bispecific antibody.In addition,the format is designed to retain favorable attributes of conventional human IgG mAbs,including their stability and predictability during manufacturing as well as the

109、ir long half-life and low immunogenicity during treatment of patients.The resulting Biclonics are bispecific heterodimeric IgG antibodies that are designed to closely mimic IgG antibodies that are produced naturally by the immune system.7 The Biclonics format also permits us to make modifications to

110、 the Fc region of the IgG antibody in order to enhance or limit effector functions associated with this part of the molecule.This strategy has been successfully executed with conventional therapeutic mAbs.In order to enhance efficacy and promote immunotherapeutic activity,we can use glycoengineered

111、cell lines used in production to generate Biclonics that are enhanced for ADCC,resulting in the improved ability to recruit NK cells and macrophages.This ADCC enhancement has been made to our most advanced bispecific antibody candidate,zenocutuzumab,and other of our antibody candidates,MCLA-158(peto

112、semtamab)and MCLA-129.In order to improve safety and tolerability,we can modify our Biclonics to prevent the excessive release of signaling proteins called cytokines,which can overstimulate the immune system.This process is called Fc-silencing,and is designed to block the ability of our Biclonics to

113、 bind to certain protein receptors on cells,known as Fc receptors,which are associated with cytokine release.We utilize Fc silencing in the design of our bispecific antibody candidate MCLA-145.High-throughput functional screening.We employ our patented Spleen to Screen technology to rapidly screen p

114、anels of new target-specific heavy chains that form common light chain binding domains,or we employ our already established panels of common light chain antibodies.To date we have discovered over 10,000 unique common light chain antibodies directed at more than 40 different antigens,including tumor-

115、associated antigens such as EGFR and c-MET;T-cell binding,stimulating or co-stimulating proteins such as CD3 and CD137(also called 4-1BB);and other immune-cell engaging antigens.For example,we have an established a panel of more than 175 unique and novel anti-CD3 common light chain antibodies from w

116、hich to discover and develop the next generation of T-cell engaging bispecific and trispecific antibodies.We then generate DNA constructs that encode target-specific human antibodies and express them in mammalian cells.The common light chain format and proprietary dimerization modifications to the C

117、H3 domain of the IgG promote the secretion of virtually pure Biclonics into the cell culture medium.The medium of thousands of cell cultures that each express a different Biclonics is harvested and individually used in high throughput molecular and cell-based functional assays to identify Biclonics

118、with specific novel characteristics for further development.For example,the chart below shows the results of a pre-clinical study in which hundreds of different Biclonics targeting HER2 and HER3 were functionally screened for cell growth inhibition of tumor cell samples in the presence or absence of

119、 the HER3 ligand NRG1.Forty of the Biclonics depicted in the chart exhibited superior inhibition of cell growth compared to trastuzumab,a drug commonly prescribed for the treatment of breast cancer,and were selected in the process leading to identification of zenocutuzumab.Advantages of Biclonics We

120、 believe our Biclonics technology platform provides the following advantages:Rapid generation of human IgG antibodies having diversity at the heavy chain targeting an array of antigens,that are ready to be paired to produce our Biclonics,bispecific antibodies.Use of our patented MeMo,Spleen to Scree

121、n,heterodimerization and Fc modification technologies,permits us to rapidly generate a large amount of diverse bispecific antibodies capable of targeting an array of antigen combinations.8 Biclonics are stable,bispecific,full-length human IgG antibodies with no linkers or fusion proteins.Biclonics r

122、etain the IgG format of antibodies that are produced naturally by the immune system.Additionally,in contrast to many other bispecific antibody formats,Biclonics do not require linkers or modifications to force the correct pairing of heavy and light chain variable regions or exploit fusion proteins t

123、o add functionality to the molecule.These qualities minimize time-consuming engineering efforts that can cause stability or developability obstacles,and instead allow us to create Biclonics with more predictable behavior during development.Our Biclonics technology platform allows for functional eval

124、uation of Biclonics in the relevant therapeutic format leading to the discovery of therapeutic candidates with novel and innovative properties.Our Biclonics technology platform permits rapid functional screening of large collections of bispecific antibodies which allows us to identify lead candidate

125、s with multiple mechanisms of action that have the potential to effectively kill tumor cells with high potency.This is an important step in the identification of lead bispecific antibody candidates with functionalities that compare favorably against other forms of therapeutics,such as conventional m

126、Abs as well as their combinations.Biclonics preserve the stability,behavior and adaptability of normal IgG antibodies.Biclonics are based on the robust and commonly used IgG format to yield the favorable in vivo qualities associated with conventional mAbs,such as stability,long half-life and low imm

127、unogenicity.As a result,our Biclonics format provides attractive options for dosage schedules and methods of administration,rendering them compatible with multiple modes of action for the efficient killing of tumor cells.Further,the IgG format allows us to apply previously established technologies t

128、o further optimize our Biclonics for therapeutic use.Biclonics can be reliably manufactured with high yields.Because our Biclonics retain the IgG format of antibodies,our Biclonics are manufactured using the large-scale industry-standard processes that are also used for the production of conventiona

129、l mAbs,and the yields of Biclonics we obtain are comparable to those of normal IgG antibodies.In stable cell lines,and using our IgG-based purification process can result in up to greater than 98%purity for our Biclonics.Our Triclonics Platform Our Triclonics technology is covered by existing Merus

130、patents and other pending applications.This format,and the suite of technologies that underpin it,permit the development of therapeutic candidates designed to bind three targets with a single multivalent molecule.In pre-clinical studies and modeling,Triclonics have shown similar qualities of a natur

131、al IgG antibody,including favorable half-life,stability,low immunogenicity and favorable developability characteristics.We believe Triclonics have the potential to produce significant specificity and potency in tumor cell-killing activity and/or to modulate the immune system to promote more robust a

132、nti-tumor immune responses,and have the potential for less on-target off-tumor toxicity.This format allows us to leverage our proprietary genetically modified MeMo mice,which as described above,harbors human heavy chain variable region gene segments and a human common light chain in its germline.MeM

133、o harnesses the power of the in vivo immune system to yield human antibodies with the potential for high affinity,specificity,optimal biophysical characteristics and low immunogenicity,which can be combined into a single trispecific antibody produced with relative high purity.The Triclonics platform

134、 employs our proprietary technologies to produce large panels of substantially pure trispecific antibodies.In addition,we have engineered a panel of novel linkers that attach a third binding domain to the antibody.This panel of linkers vary in properties such as length and flexibility,and are empiri

135、cally selected for stability and other drug-like properties,while remaining stable and are predicted to have low immunogenicity.The linker panel provides another lever of flexibility in optimizing functional characteristics in our high-throughput screening while maintaining high quality,stability an

136、d limiting risk of immunogenicity.9 One application of the Triclonics platform is as a T-cell engager for solid tumors.By binding to three targets,we can generate Triclonics designed to specifically engage a combination of two tumor antigens for enhanced specificity,binding preferentially to tumor c

137、ells expressing both antigens,over normal tissues that may express either antigen,but not both or both at lower expression levels.In this construct,the third binding domain can,for example,engage an innate or adaptive immune effector cell protein,to stimulate killing of the tumor cell.We believe our

138、 Triclonics platform will permit us to develop molecules with enhanced on-target,on-tumor specificity,while optimally engaging the immune system mechanisms and potentially having greater potency and a larger therapeutic window.Our process to select lead Triclonics leverages our patented MeMo and Spl

139、een to Screen human antibody generation and heterodimerization technologies,along with our proprietary linkers based on natural structures to undertake high throughput unbiased functional screening of Triclonics.With this approach,we have been able to evaluate up to 1,800 different trispecific antib

140、odies targeting three different antigens to identify those unique combinations that pre-clinically have been observed to have desired characteristics for further development.Our Bispecific and Trispecific Antibody Candidate Portfolio We currently have four bispecific antibody candidates in clinical

141、development,with additional bispecific and trispecific programs in pre-clinical development.Zenocutuzumab(MCLA-128,HER3 x HER2 Biclonics)Zenocutuzumab is an antibody-dependent cell-mediated cytotoxicity(ADCC)-enhanced Biclonics that utilizes Merus Dock&Block mechanism to bind to HER2,and bind to and

142、 disrupt the interaction between HER3 and ligand,NRG1 or mutated form NRG1 fusion,in solid tumors.HER2,or human epidermal growth factor receptor 2,is amplified in many solid tumors and is associated with poor prognosis,and the activation of HER3,or human epidermal growth factor receptor 3,is associa

143、ted with tumor progression and treatment resistance.On the surface of tumor cells,HER2 pairs,or dimerizes,with HER3,and the resulting pair drives malignant progression of HER2-expressing cancer cells.NRG1,which is the ligand for HER3,causes cancer cells to grow and become resistant to treatment with

144、 HER2-targeted therapies.Zenocutuzumab is believed to target the HER3 signaling pathway by disrupting the interaction of HER3 with its ligand NRG1 and to overcome the resistance of tumor cells to HER2-targeted therapies using two mechanisms:blocking growth and survival pathways to stop tumor expansi

145、on and recruitment,and ADCC-enhanced elimination of the tumor via effector cells.In addition,we have identified a rare,genetically defined patient population whose cancers harbor NRG1 fusions.The NRG1 gene encodes for neuregulin,the ligand for HER3.Fusions between NRG1 and other genes in the genome

146、are rare genetic events occurring in solid tumors,and are associated with activation of HER2/HER3 signaling and growth of cancer cells.The NRG1 fusion is a powerful driver of cancer cell growth.We believe that pre-clinical studies and clinical evaluation indicate zenocutuzumab(binding to HER2 and bl

147、ocking NRG1 fusion protein interaction with HER3)has the potential to be particularly effective against tumors harboring NRG1 fusions.10 DevelopmentIn our pre-clinical studies,the administration of zenocutuzumab resulted in the inhibition of NRG-induced growth in cultures of cancer cells.Zenocutuzum

148、ab also blocked activation of two key signaling pathways for the growth and survival of tumor cells more than Herceptin(trastuzumab)or the combination of Herceptin and Perjeta(pertuzumab)(shown in red below)or experimental anti-HER3 mAbs(shown in green below).See Geuijen et al.Cancer Cell(2018).*ind

149、icates analog antibodies.In a patient-derived tumor xenograft mouse model(PDX model),zenocutuzumab significantly blocked tumor growth of a cancer containing an NRG1 gene fusion.11 Based on encouraging pre-clinical results,we initiated a phase 1/2 study of zenocutuzumab in solid tumors.NRG1 Fusions a

150、nd other potential cancers through targeting HER2 and HER3 We are currently enrolling patients for the phase 1/2 eNRGy trial to assess the anti-tumor activity of monotherapy zenocutuzumab in NRG1+cancers.The eNRGy trial enrolls patients with NRG1+solid tumors.Enrolled patients will receive 750 mg of

151、 zenocutuzumab every two weeks.In June 2019,we opened a zenocutuzumab Early Access Program(EAP)and amended the phase 1/2 trial to focus on patients with solid tumors harboring an NRG1 fusion(the eNRGy trial).Patients treated under EAP and the protocol amendment receive zenocutuzumab at 750 mg admini

152、stered intravenously every other week.In January 2021,the FDA granted Fast Track designation of zenocutuzumab for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions that have progressed on standard-of-care therapy.In June 2022,we provided an update on the eNRGy trial

153、and EAP at the American Society for Clinical Oncology Annual Meeting(ASCO).The interim data,as of an April 12,2022 efficacy data cutoff date,included zenocutuzumab treatment of 110 patients with NRG1+pancreatic,NSCLC,and other cancers,79 of whom were evaluable with measurable disease having the oppo

154、rtunity for six months or more follow-up and who met the criteria for the primary analysis with a median age of 59(range 22-84).Partial responses(PRs)by Response Evaluation Criteria in Solid Tumors(RECIST)criteria version 1.1 as assessed by investigator review was 34%(95%CI;24%-46%)across multiple t

155、umor types.Tumor shrinkage was observed in 70%of patients.Median time to response was 1.8 months,and a median duration of exposure was 6.3 months.Median duration of response was 9.1 months,and 20/83 patients were continuing treatment as of the cutoff date.12 Zenocutuzumab was observed to have a favo

156、rable and tolerable safety profile(across 208 patients treated with zenocutuzumab monotherapy as of the January 12,2022 safety data cutoff date).The majority of adverse events were mild or moderate(Grade 1 or 2)in severity,and an absence of severe gastrointestinal and skin toxicities and clinical ca

157、rdiotoxicity,and a low incidence(15%)of infusion reactions was observed.In October 2022,we met with the U.S.Food and Drug Administration(FDA)regarding a potential Biologics License Application(BLA)filing for Zeno in NRG1+cancer.Based on the FDA feedback,we believe multiple registrational paths remai

158、n viable,and have decided the optimal approach is to sequence its development plan by first seeking a potential application for NRG1+lung and/or pancreatic cancer,which could then be followed by a potential tissue agnostic filing.We believe Zeno has the potential to be both first in class and best i

159、n class,and a new standard of care for the treatment of NRG1+cancer.We plan to provide an update on the potential registrational path and timeline in NRG1+cancer in the first half of 2023 and a clinical update on Zeno in NRG1+cancer at a major medical conference in 2023.Further,we are evaluating a c

160、ohort exploring the combination of zenocutuzumab in addition to enzalutamide or abiraterone,an androgen deprivation therapy in CRPC,irrespective of NRG1+status.Further,we are evaluating a cohort exploring the combination of zenocutuzumab and afatinib for patients with NRG1+NSCLC.We plan to provide a

161、n initial clinical update on zenocutuzumab in CRPC in the second half of 2023.Petosemtamab(MCLA-158,EGFR x LGR5 Biclonics)Petosemtamab,is an investigational antibody-dependent cell-mediated cytotoxicity(ADCC)-enhanced Biclonics for the potential treatment of solid tumors that is designed to bind to

162、cancer stem cells expressing leucine-rich repeat-containing G protein-coupled receptor 5(LGR5)and EGFR.LGR5 is a WNT target gene expressed in cancer cells with aberrations in the WNT signaling pathway,while EGFR is a member of the HER family of receptor tyrosine kinases and is important for growth a

163、nd survival of cancer stem cells,including those with RAS mutations.Petosemtamab is designed to use two different mechanisms of action.The first is intended to block growth and survival pathways in cancer stem cells.The second involves the recruitment and enhancement of immune effector cells in an e

164、ffort to directly kill cancer stem cells that persist in solid tumors and cause relapse and metastasis.DevelopmentIn our pre-clinical studies,petosemtamab demonstrated superior growth inhibition and selectivity versus the EGFR-targeting mAb,cetuximab.Petosemtamab was significantly more potent than c

165、etuximab in inhibiting the growth of patient-derived colorectal cancer organoids.Additionally,petosemtamab was observed to be selectively more active in human tumor-derived organoids than in organoids derived from normal human colon.The activity of petosemtamab on the tumor organoid size was more th

166、an 100 times greater than on the normal colon organoids.In contrast,the activity of cetuximab was similar to the activity of petosemtamab on normal colon organoids and 20 to 100 times less than the activity of petosemtamab on tumor organoids.These ex-vivo observations of petosemtamab with organoid m

167、odels were further observed in vivo in xenograft models generated from the same patient-derived organoids.In our pre-clinical studies,petosemtamab further demonstrated significant induction of internalization of EGFR and LGR5,resulting in EGFR degradation,and elicited potential anti-tumor activity i

168、n patient-derived esophageal,gastric and HNSCC xenograft models.13 14 Solid Tumors Petosemtamab is currently being evaluated in a phase 1 open-label,multicenter study,and is in the expansion phase,in patients with solid tumors.The primary endpoint is safety and tolerability of the defined dose;secon

169、dary endpoints include single-agent preliminary anti-tumor activity.The recommended phase 2 dose was established at 1500 mg administered intravenously once every two weeks.Enrollment continues at this dose in the expansion phase of the open-label,multicenter trial.In October 2021,we presented interi

170、m clinical data from the ongoing phase 1 dose expansion cohort that is investigating the safety,tolerability,and anti-tumor activity of petosemtamab,including clinical responses observed in advanced HNSCC,at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeu

171、tics.As of the efficacy data cutoff date of August 9,2021,10 patients with advanced HNSCC were enrolled,with median age of 65(range 50-77)years,and who were treated with a median of 2 lines of prior therapy.Seven patients were evaluable for an interim efficacy analysis by investigator assessment(thr

172、ee patients were enrolled 8 weeks from the cutoff date).Three of seven patients achieved partial responses,with one of these three achieving complete response after the data cutoff date.Tumor reduction was observed in all seven patients.The safety results for petosemtamab were based on 29 patients w

173、ith advanced solid tumors who were treated at 1500 mg every two weeks across the phase 1 trial.The most frequent adverse events were infusion related reactions;72%any grade,7%grade 3 and mild to moderate skin toxicity;3%grade 3.We plan to provide a clinical update on petosemtamab in the first half o

174、f 2023 at a medical conference.The planned update will include data from approximately 40 patients with HNSCC with meaningful clinical follow up,and data from patients with gastro-esophageal cancer,to inform clinical development strategy.We further plan to provide a regulatory path update on petosem

175、tamab in the first half of 2023.MCLA-129(EGFR x c-MET Biclonics)MCLA-129 is an investigational Biclonics,designed to bind EGFR and c-MET,for the potential treatment of solid tumors.EGFR is an important oncogenic driver in many cancers.The upregulation of c-MET signaling has been associated with resi

176、stance to EGFR inhibition.MCLA-129 has two distinct mechanisms of action.First,MCLA-129 is designed to block the signaling of EGFR as well as c-MET,in an effort to inhibit tumor growth and survival.Second,MCLA-129 utilizes ADCC-enhancement technology,which is designed for greater cell-killing potent

177、ial.MCLA-129 is being developed in collaboration with Betta Pharmaceuticals Co.Ltd.(Betta).Under the terms of the collaboration,Betta is responsible for the clinical development and commercialization of MCLA-129,if approved,in China and we retain all rights to MCLA-129 outside of China.In January 20

178、21,Betta announced that the Chinese National Medical Products Administration had accepted its IND for MCLA-129 injection and in October 2021,Betta announced that the first patient was dosed in Bettas sponsored phase 1/2 trial of MCLA-129 in China in patients with advanced solid tumors.Development15

179、Pre-clinical data on MCLA-129 were presented in October 2019,at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.The poster,entitled“Pre-clinical evaluation of MCLA-129:a bispecific antibody targeting c-MET and EGFR,”showed that MCLA-129 inhibited and reversed

180、 resistance to tyrosine kinase resistant NSCLC,cell lines resulting in tumor growth inhibition in xenograft models of NSCLC.In these xenograft models,MCLA-129 showed tumor shrinkage in mice whose tumors are resistant to the EGFR small molecule inhibitor erlotinib.MCLA-129 Inhibited TKI Resistant NSC

181、LC|MCLA-129 Reversed Acquired TKI Resistance We believe these pre-clinical data suggest MCLA-129,if successfully developed and approved,could benefit patients having NSCLC that become resistant to EGFR targeted therapies.Solid Tumors In May 2021,we commenced a phase 1/2 dose escalation and expansion

182、 trial evaluating MCLA-129 for the treatment of patients with advanced non-small cell lung cancer and other solid tumors.The MCLA-129 trial is ongoing in the dose expansion phase,treating patients with MCLA-129 monotherapy in c-MET exon 14 mutant(m)NSCLC,EGFRex20 NSCLC,HNSCC,as well as in combinatio

183、n with Tagrisso(osimertinib)a third generation EGFR tyrosine kinase inhibitor(TKI)in treatment naive EGFRm NSCLC and in patients with EGFRm NSCLC that have progressed on Tagrisso.In October 2022,we presented interim data from the ongoing phase 1/2 trial at the 34th EORTC/NCI/AACR Symposium on Molecu

184、lar Targets and Cancer Therapeutics(ENA Symposium).As of a May 8,2022 cutoff date,20 patients were treated with MCLA-129 across doses of 100,300,600,1000 and 1500 mg every two weeks.These patients were followed for safety and efficacy through a data cutoff of August 15,2022,with 18 evaluable for eff

185、icacy,with two discontinuing before the second infusion.As of the August 15,2022 cutoff date,the median age of patients was 65.5 years(range:43-79),tumor types enrolled included 14 patients with EGFR m NSCLC(8 Del19,4 L858R,1 EGFRex20,1 other),2 patients with c-MET exon 14 m NSCLC,1 patient with c-M

186、ET amplified gastric adenocarcinoma,1 patient with esophageal squamous cell carcinoma,1 patient with HNSCC.Antitumor activity was observed by investigator review,including 2 confirmed partial responses,and 4 additional patients with observed tumor shrinkage of greater than 20%.Time on treatment incl

187、uded a median duration of exposure of 12.6 weeks(range:3-43 weeks),with 6 of 20 patients remaining ongoing as of the August 15,2022 data cutoff,with the following internal safety and efficacy data presented:16 As of the August 15,2022 cutoff date,MCLA-129 was observed to be well tolerated based on 2

188、0 patients who received one or more doses of MCLA-129 across the dose levels tested.No dose limiting toxicities(DLTs)were reported.The most frequent adverse events(AEs)were infusion-related reactions(IRR),with 90%of patients observed to experience IRR AEs of any grade,one patient(5%)experienced a gr

189、ade 3,and no grade 4 or 5 AEs were observed.The majority of AEs occurred during the first infusion,with no treatment-related grade 4 or 5 AEs reported,and no interstitial lung disease reported.Based on the pharmacokinetic and pharmacodynamic data,and these interim safety results an initial recommend

190、ed phase 2 dose was selected at 1500 mg every two weeks.We plan to provide an initial clinical data update from the expansion cohorts,and a further clinical development strategy update in the second half of 2023.MCLA-145(CD137 x PD-L1 Biclonics)MCLA-145 is a Biclonics T-cell engager that binds to hu

191、man programmed death-ligand 1(PD-L1)and CD137.MCLA-145 is designed to recruit,activate and prevent the exhaustion of tumor-infiltrating T cells,and to cause a potent and durable T-cell activation in the tumor microenvironment.MCLA-145s binding to a cell is predicted to lead to clustering of CD137 on

192、 T cells when PD-L1 is expressed on adjacent cells,and block the T-cell inhibitory PD-1/PD-L1 interactions in the tumor.Developed by Merus through an unbiased functional screening of multiple immunomodulatory target combinations,the unique immunostimulatory profile of MCLA-145 derives from the poten

193、tial to potently activate immune effector cells in the context of the tumor microenvironment while blocking inhibitory signals among T-cells within the same immune cell population.DevelopmentIn our pre-clinical studies,MCLA-145 showed binding to PD-L1 and CD137,recruitment of T cells into the tumor,

194、blocking of inhibitory PD-1/PD-L1 axis and potent T-cell activation.17 Further,MCLA-145 demonstrated superior tumor cell killing as compared to the administration of a combination of monospecific anti-PD-L1 and anti-CD137 antibodies in PDX models.Solid Tumors MCLA-145 is currently enrolling a global

195、,phase 1,open-label,single-agent clinical trial evaluating MCLA-145 in patients with solid tumors.The trial consists of a dose escalation phase,followed by a planned dose expansion phase.We are also evaluating the combination of MCLA-145 with a Keytruda(pembrolizumab)PD-1 blocking antibody with enro

196、llment ongoing.In May 2019,we commenced a phase 1 open-label,single-agent clinical trial of MCLA-145,consisting of dose escalation followed by dose expansion,for the potential treatment of patients with advanced solid tumors.The primary objectives of the phase 1 trial are dose finding and evaluation

197、 of safety and tolerability in patients.The trial will also examine potential preliminary antitumor activity and functional target engagement of single-agent MCLA-145.In December 2021,we presented interim clinical data on MCLA-145 from the phase 1 trial in patients with solid tumors at the ESMO Immu

198、no-Oncology Congress 2021.As of the data cutoff date of July 14,2021,34 patients with advanced or metastatic solid tumors with median age of 60.5(range 27-81)years had been treated at 8 dose levels ranging from 0.4-75mg Q2W.The median(range)duration of treatment with MCLA 145 was approximately 6(174

199、)weeks.Reported adverse events(AEs)were generally managed 18 with drug interruption and/or administration of steroids in some patients.Treatment-emergent AEs(TEAEs)occurred in 33 patients(97.1%)and treatment-related TEAEs occurred in 23 patients(67.6%),most commonly fatigue(n=6,17.6%)and decreased n

200、eutrophil count(n=6,17.6%).Dose limiting toxicities(DLTs),defined as within 28 days from the first infusion,occurred in 4 patients(11.8%).Laboratory alanine transaminase/aspartate transaminase(ALT/AST)elevations of any grade were observed in 15 patients(44.1%),with grade 3 ALT/AST elevations in 6 pa

201、tients(17.6%).Preliminary evidence of antitumor activity has been observed at doses 25 mg biweekly.Analysis of peripheral blood showed robust T-cell activation,including activation of cytotoxic CD8+cells and cytokines,across the 10 to 75 mg biweekly dosing range.Pre-clinical Discovery Programs We in

202、tend to further leverage our Biclonics and Triclonics technology platforms to identify multiple additional antibody candidates and advance them to clinical development.Each of these antibody candidates are designed to bind to targets believed to be useful in the treatment of cancer with an intention

203、 to establish efficacy and obtain information for submission to the FDA.Using our patented platforms,we will continue to evaluate new targets and combinations to identify potential candidates with the highest therapeutic potential and select those candidates to be advanced into clinical trials.Colla

204、boration Agreements As part of our business strategy,we collaborate with a range of partners,including pharmaceutical,biotechnology,and diagnostic companies,as well as academic institutions.We intend to continue to seek collaborations and license agreements to develop and commercialize therapeutics

205、in order to exploit the potential of our Biclonics and Triclonics platforms.Incyte Corporation We have entered into a collaboration and license agreement(Collaboration Agreement)with Incyte Corporation(Incyte).Under the terms of the Collaboration Agreement,we and Incyte have agreed to collaborate wi

206、th respect to the research,discovery and development of monospecific or bispecific antibodies utilizing our proprietary Biclonics technology platform.Following the election by Incyte to opt-out of its ex-U.S development of MCLA-145,discussed below,the collaboration encompasses up to 10 independent p

207、rograms.We have the option to co-fund development of products,if any,arising from one specified program,and subject to certain conditions,to a second specified program,in each case in exchange for a share of profits in the United States,as well as the right to participate in a specified proportion o

208、f detailing activities in the United States for one of such programs.If we exercise our co-funding option for a program,we would be responsible for funding 35%of the associated future global development costs and,for certain of such programs,would be responsible for reimbursing Incyte for certain de

209、velopment costs incurred prior to the option exercise.All products as to which we have exercised our option to co-fund development would be subject to joint development plans and overseen by a joint development committee,with Incyte having final determination as to such plans in cases of dispute.For

210、 one of our current clinical programs,concerning MCLA-145,under the Collaboration Agreement,Incyte had received the exclusive right to develop and commercialize the product candidate outside the United States.In January 2022,we announced that Incyte elected to opt-out of its ex-U.S.development of MC

211、LA-145,restoring full global rights to Merus.Under the terms of the Collaboration Agreement,Incyte supported the program for a limited time while ex-U.S.activities transitioned to Merus.Incyte retains a right to a residual royalty of up to 4%on sales of future commercialization of MCLA-145,if approv

212、ed.19 For each program,where we have not elected to co-fund development or where we do not have such a co-funding option and which has not been dropped or terminated by Incyte,Incyte is solely responsible for all costs of global development and commercialization activities.We retain the rights to,am

213、ong other things,our Biclonics technology platform as well as clinical and pre-clinical candidates and future programs emerging from our platform that are outside the scope of the Collaboration Agreement.In January 2017,upon the Collaboration Agreement becoming effective,Incyte made an upfront non-r

214、efundable payment to us of$120 million for the rights granted under the Collaboration Agreement.For each program as to which we do not have commercialization or co-development rights,we are eligible to receive up to$100 million in future contingent development and regulatory milestones and up to$250

215、 million in commercialization milestones,as well as tiered royalties ranging from 6%to 10%of global net sales.For each program as to which we have exercised our option to co-fund development,we are eligible to receive a 50%share of profits(or sustain 50%of any losses)in the United States and tiered

216、royalties ranging from 6%to 10%of net sales of products outside of the United States.If we opt to cease co-funding a program as to which we exercised our co-development option,then we will no longer receive a share of profits in the United States but will be eligible to receive the same milestones f

217、rom the co-funding termination date and the same tiered royalties described above with respect to non-co-developed programs and,depending on the stage at which we choose to cease co-funding development costs,additional royalties ranging up to 4%of net sales in the United States.The Collaboration Agr

218、eement will continue on a program-by-program basis until neither party has any royalty payment obligations with respect to such program or,if earlier,the termination of the Collaboration Agreement or any program in accordance with the terms of the Collaboration Agreement.The Collaboration Agreement

219、may be terminated in its entirety,or on a program-by-program basis,by Incyte for convenience.The Collaboration Agreement may also be terminated by either party under certain other circumstances,including material breach,or on a program-by-program basis for patent challenge of patents under the appli

220、cable program,in each case as set forth in the Collaboration Agreement.If the Collaboration Agreement is terminated in its entirety or with respect to one or more programs,all rights in the terminated programs revert to us,subject to payment to Incyte of a reverse royalty of up to 4%on sales of futu

221、re products,if we elect to pursue development and commercialization of products arising from the terminated programs.In connection with the Collaboration Agreement,we entered into a Share Subscription Agreement with Incyte,pursuant to which,in January 2017,we issued and sold to Incyte 3,200,000 comm

222、on shares for an aggregate purchase price of$80.0 million.Eli Lilly and Company(Eli Lilly)In 2021,we entered into a collaboration and license agreement(the Lilly Collaboration Agreement)and share subscription agreement(the“Lilly Subscription Agreement”)with Eli Lilly and Company,an Indiana corporati

223、on(Eli Lilly).Under the terms of the Lilly Collaboration Agreement,we and Eli Lilly agreed to collaborate with respect to the discovery and research of bispecific antibodies utilizing our proprietary Biclonics bispecific technology platform.The collaboration encompasses up to three(3)independent pro

224、grams directed to the generation of T-cell re-directing bispecific antibodies that bind CD3 and a tumor associated antigen target selected by Eli Lilly(Target)to be the subject of each such program.We granted to Eli Lilly an exclusive,worldwide,royalty-bearing,sublicensable license,under certain pat

225、ent rights and know-how to exploit certain compounds and products directed to designated Targets in combination with CD3,or directed to such designated Target(s)alone as a monospecific antibody or monospecific antibody drug conjugate,subject to rights granted by us to third parties under one or more

226、 existing third-party agreements.We also retain all rights not granted to Eli Lilly.Additionally,in the case of a change of control that may adversely impact certain rights and obligations of us and Eli Lilly under the Lilly Collaboration Agreement,(a)we have agreed to terminate or transfer its righ

227、ts to third parties under certain research programs and(b)Eli Lilly has the option to take over certain of our research obligations.Eli Lilly paid an upfront,non-refundable payment of$40 million for the rights granted under the Lilly Collaboration Agreement.Eli Lilly agreed to fund the research and

228、development activities we conduct for each program under an agreed research plan and budget.With respect to each product arising from each program,we are eligible to receive up to$290 million in future contingent development and regulatory milestones and up to$250 million in commercial sales milesto

229、nes,for a total of up to approximately$1.6 billion for a single product generated from all three programs.We are further eligible to receive,on a product-by-product and country-by-country basis,tiered royalties based on the level of worldwide aggregate annual net sales at percentages ranging from th

230、e mid-single digits to low double digits until the royalty term expires.The Lilly Collaboration Agreement includes a three-year research term for us to perform research and development activities,subject to two extension terms of six months at Eli Lillys discretion.The Lilly Collaboration Agreement

231、will continue on a product-by-product basis until Eli Lilly has no royalty payment obligations with respect to such product or,if earlier,the termination of the Lilly Collaboration Agreement or any program in accordance with the terms of the Lilly Collaboration Agreement.The Lilly Collaboration Agre

232、ement may be terminated in its entirety or on a program-by-program basis at will by Eli Lilly.The Lilly Collaboration Agreement may also be terminated by either us or Eli Lilly under certain other circumstances,including material breach,as set forth in the Lilly Collaboration Agreement.If the Lilly

233、Collaboration Agreement is terminated with respect to one or more programs,depending on the stage of development,certain rights in the terminated programs revert to us,in accordance with the terms of the Lilly Collaboration Agreement.20 Also in January 2021,in connection with entering into the Lilly

234、 Collaboration Agreement,pursuant to the Lilly Subscription Agreement,Eli Lilly agreed to purchase 706,834 common shares of the Company at a price per share of$28.295 for aggregate gross proceeds to us of approximately$20 million(the“Private Placement”).Ono Pharmaceutical Co.,Ltd.In April 2014,we en

235、tered into a strategic research and license agreement with Ono,under which we granted Ono an exclusive,worldwide,royalty-bearing license to research,test,make,use and market a limited set of bispecific antibody candidates,if approved,based on our Biclonics technology platform,directed to two undiscl

236、osed targets.Ono paid us a non-refundable upfront fee of 1.0 million,and we are eligible to receive up to an aggregate of 57.0 million in milestone payments upon achievement of specified research and clinical development milestones.For products commercialized under this agreement,if any,we are also

237、eligible to receive a mid-single digit royalty on net sales.For a designated period,which may include limited time periods following termination of this agreement,in certain circumstances we and our affiliates are prohibited from researching,developing or commercializing bispecific antibodies agains

238、t the target combination that are the subject of this agreement.Ono also provides funding for our research and development activities under an agreed-upon plan.This research and license agreement will expire after all milestone payments have been received and all related patent rights have expired,u

239、nless terminated earlier.Ono has the right to terminate this agreement at any time for any reason,with or without cause.The licenses granted to Ono may convert to royalty-free,fully-paid,perpetual licenses if Ono terminates the agreement for uncured material breach.We retain all rights to use and co

240、mmercialize any antibodies directed to one target utilized under the collaborative research program,and any antibodies directed to the second target developed under the collaborative research program,excluding the up to five lead and/or selected antibodies against the second target Ono is pursuing,p

241、rovided that the use and commercialization is not with respect to the particular target combination.To date,we have achieved five of the specified milestones under this research and license agreement and have received an aggregate of 4.7 million in milestone payments.On March 14,2018,we entered into

242、 a second contract research and license agreement with Ono.Pursuant to an exclusive option granted to Ono in the prior agreement executed in April 2014,Ono exercised its option to enter into the March 2018 agreement.We granted Ono an exclusive,worldwide,royalty-bearing license,with the right to subl

243、icense,research,test,make,use and market bispecific antibody candidates based on our Biclonics technology platform against two undisclosed targets directed to a particular undisclosed target combination.Ono identifies and selects the licensed bispecific antibodies for which it is responsible for con

244、ducting further non-clinical and clinical development activities for such licensed bispecific antibodies and pharmaceutical products containing such antibodies,including manufacture and process development.Ono controls and has exclusive rights over the worldwide commercialization of any approved pro

245、ducts,including worldwide supply,and is solely responsible for all costs and expenses related to commercialization.Ono has agreed to fund our research and development activities and be responsible for the payment of all costs and expenses for its own research and development activities,which are set

246、 out in a mutually agreed upon research plan.We retain all rights to use and commercialize any antibodies that are generated under the collaborative research program,excluding the up to five lead and/or selected antibodies against the targets Ono is pursuing,provided that the use and commercializati

247、on is not with respect to the particular target combination.As part of the 2018 agreement,Ono agreed to pay an upfront non-refundable payment of 0.7 million for the rights granted and we are also eligible to receive an additional aggregate of 57.0 million in milestone payments upon achievement of sp

248、ecified research and clinical development milestones.In the fourth quarter of 2022,Merus achieved a milestone payment of 1.0 million from Ono for preclinical advancement of a lead candidate arising from this license.To date,we have achieved four of the specified pre-clinical milestones under this re

249、search and license agreement and have received an aggregate of 2.7 million in milestone payments.For products commercialized under the License Agreement,if any,the Company is eligible to receive a mid-single digit royalty on net sales.For a designated period,which may include limited time periods fo

250、llowing termination of this agreement,in certain circumstances we are prohibited from researching,developing or commercializing bispecific antibodies against the undisclosed target combination that are the subject of this agreement.Ono also provides funding for our research and development activitie

251、s under an agreed-upon plan.This research and license agreement will expire after all milestone payments have been received and all related patent rights have expired,unless terminated earlier.Ono has the right to terminate this agreement at any time for any reason,with or without cause.The licenses

252、 granted to Ono may convert to royalty-free,fully-paid,perpetual licenses if Ono terminates the agreement for uncured material breach.Betta Pharmaceuticals Co.Ltd.On December 10,2018,we entered into a collaboration and license agreement with Betta Pharmaceuticals Co.Ltd.(Betta)where we granted Betta

253、 an exclusive license to develop and commercialize MCLA-129 in China.We retain all rights outside of China.Under the terms of the agreement,Betta retained a contract manufacturing organization with experience in filing IND applications with U.S.authorities and clinical trial applications(CTAs)with E

254、uropean regulatory authorities in order to produce clinical trial materials for the Chinese market and the rest of the world.21 In addition to a non-refundable upfront payment,we and Betta will share equally the cost of the transfer of the manufacturing technology to a contract manufacturing organiz

255、ation.We are also eligible to receive an aggregate of$12.0 million in milestone payments contingent upon Betta achieving certain specified development and commercial goals as well as tiered royalty payments of net sales of any products resulting from the collaboration in China.Betta is eligible to r

256、eceive milestone payments contingent upon us achieving certain specified development and commercial goals,and is eligible to receive tiered royalty payments of net sales outside of China.Manufacturing Our Biclonics technology platform relies on third parties for biological materials.We rely on and e

257、xpect to continue to rely on third-party contract manufacturing organizations(CMOs)for the supply of current good manufacturing practice-grade(cGMP-grade)clinical trial materials and commercial quantities of our antibody candidates and products,if approved.We currently do not have any agreements for

258、 the commercial production of product candidates,but we have contracted several biopharmaceutical CMOs for the clinical manufacture of zenocutuzumab,MCLA-158 or petosemtamab,MCLA-129 and MCLA-145.We believe that the standardized Biclonics manufacturing process can be transferred to additional CMOs a

259、nd potential future co-development or co-commercialization collaborations or partnerships for the production of clinical and commercial supplies of our Biclonics in the ordinary course of business.Sales and Marketing We have not yet defined our sales,marketing or product distribution strategy for ze

260、nocutuzumab,petosemtamab,MCLA-129,MCLA-145 or any of our other antibody candidates because our antibody candidates are still in pre-clinical or early-to-middle-stage clinical development.We hired an Executive Vice President&Chief Commercial Officer in February 2022,to lead the commercial strategy fo

261、r Merus pipeline of multispecific product candidates in development.Our commercial strategy may include the use of strategic partners,distributors,a contract sales force,or the establishment of our own commercial and specialty sales force.We plan to further evaluate these alternatives as we approach

262、 approval,if any,for one of our antibody candidates.CompetitionWe compete directly with companies that focus on oncology and companies dedicating their resources to cancer therapies.We also face competition from academic research institutions,governmental agencies and other various public and privat

263、e research institutions.With the proliferation of new drugs and therapies into oncology,we expect to face increasingly intense competition as new technologies become available and new therapeutic candidates are clinically developed or approved therapies are explored for new indications.Any antibody

264、candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.Many of our competitors have significantly greater financial,manufacturing,marketing,drug development,technical and human resources than we do.Merg

265、ers and acquisitions in the pharmaceutical,biotechnology and diagnostic industries may result in even more resources being concentrated among a smaller number of our competitors.Smaller or early-stage companies may also prove to be significant competitors,particularly through collaborative arrangeme

266、nts with large and established companies.These competitors also compete with us in recruiting and retaining top qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials,manufacturers production capacity,as well as in acquiring t

267、echnologies complementary to,or necessary for,our programs.The key competitive factors affecting the success of all of our therapeutic antibody candidates,if approved,are likely to be their efficacy,safety,dosing convenience,price,the effectiveness of companion diagnostics in guiding the use of rela

268、ted therapeutics,the level of generic competition and the availability of reimbursement from government and other third-party payors.Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer,more effective,less expensive,more conve

269、nient or easier to administer,or have fewer or less severe side effects than any products that we may develop.Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours,which could result in our competitors establishing a str

270、ong market position before we are able to enter the market.Even if our antibody candidates achieve marketing approval,they may be priced at a significant premium over competitive products if any have been approved by then.In addition to currently marketed therapies,there are also a number of product

271、s in late-stage clinical development to treat cancer,including other bispecific antibodies or similar molecules.Our closest competitors in this area include Genmab A/S,Inhibrx,Inc.,Janssen Pharmaceutical Companies,MacroGenics,Inc.,Regeneron Pharmaceuticals,Inc.and Xencor,Inc.The antibody candidates

272、in development by competitors may provide efficacy,safety,dosing convenience and other benefits that are not provided by currently marketed therapies.As a result,they may provide significant competition for any of our antibody candidates for which we obtain marketing approval.22 Intellectual Propert

273、yWe strive to protect and enhance the proprietary technologies,inventions,and improvements that we believe are important to our business,including seeking,maintaining,and defending patent rights,whether developed internally or licensed from third parties.Our policy is to seek to protect our propriet

274、ary position by,among other methods,pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States related to our proprietary technology,inventions,improvements,platforms and antibody candidates that are important to the development and implementation

275、 of our business.As of January 31,2023:Our patent portfolio related to our bispecific antibody candidate zenocutuzumab comprises one application filed under the Patent Cooperation Treaty(PCT)application,filed on February 27,2015 with two issued patents in Europe,one in the United States and 11 other

276、 foreign jurisdictions and applications pending in Europe,the United States and 11 other foreign jurisdictions with an expected expiry not earlier than February 2035.Claims are directed to the zenocutuzumab composition of matter and methods of using zenocutuzumab to treat subjects having or at risk

277、of having a HER2 and/or HER3 positive tumor.In addition,our portfolio includes six PCT patent applications covering further methods of using zenocutuzumab,including in combination therapies to treat patients,concerning methods of treating patients with cancer harboring NRG1 gene fusions,patients wit

278、h certain forms of HER3 positive tumors.One of these PCT applications was filed on April 3,2018,with issued claims in one foreign jurisdiction and applications pending in Europe,the United States and 17 other foreign jurisdictions,with an expiry date no later than April 2038.Claims are directed to m

279、ethods of treatment using zenocutuzumab,including in combination with an HER2 targeting agent in patients with an HER2/HER3 positive tumor,like a tumor in the breast or brain.The second of these PCT applications was filed on April 3,2018,with applications pending in Europe,the United States and four

280、 other foreign jurisdictions,with an expiry date no later than April 2038.Claims are directed to methods of treatment using zenocutuzumab in patients having an HER2/HER3 positive tumor but not previously treated with a HER2 specific therapy or with a HER3 specific therapy.The third of these PCT appl

281、ications was filed on April 3,2018,with issued claims in one foreign jurisdiction and applications pending in Europe,the United States and 17 other foreign jurisdictions,with an expiry date no later than April 2038.Claims are directed to methods of treating patients with cancers harboring NRG1 gene

282、fusions.The fourth of these PCT applications was filed on May 17,2018,with issued claims in two foreign jurisdictions and applications pending in Europe,the United States and 15 other foreign jurisdictions,with an expiry date no later than May 2038.Claims are directed to methods of treatment using z

283、enocutuzumab,including in combination with endocrine therapy of patients with cancers,such as hormone receptor positive breast cancer.The fifth of these PCT applications was filed on October 23,2020,with applications pending in Europe,the United States and seven other foreign jurisdictions,with an e

284、xpiry date no later than October 2040.Claims are directed to methods of treatment using zenocutuzumab in patients with NRG1 positive cancers,including in patients that progressed after having received prior treatment certain treatment.The sixth of these PCT applications was filed on November 3,2021,

285、with national phase entry due in May of 2023.Claims are directed to treatment of patients with certain HER3 positive cancers using zenocutuzumab.Our patent portfolio related to our CD3 technology comprises a first PCT application,filed on July 8,2016,with issued patents in the United States,Europe a

286、nd one foreign jurisdiction,and applications pending in the United States,Europe and 12 foreign jurisdictions with an expected expiry not earlier than July 2036.A second PCT application was filed on March 27,2020,with applications pending in the United States,Europe,and 19 foreign jurisdictions with

287、 an expected expiry not earlier than March 2040.Claims are related to the anti-CD3 binding domains,antibodies,their use,among other subject matter.Our patent portfolio related to our bispecific antibody candidate petosemtamab comprises one PCT filed on October 21,2016,with one issued patent in Europ

288、e,four issued patents in foreign jurisdictions and applications pending in Europe,the United States and 13 other foreign jurisdictions with an expiry no earlier than October 2036.Claims are directed to the petosemtamab composition of matter and methods of using petosemtamab in the treatment or preve

289、ntion of various solid tumors.In addition,our portfolio includes four PCT applications,one of which was filed on August 19,2020,with applications pending in Europe,the United States and 18 other foreign jurisdictions with an expiry no earlier than August 2040.Claims are directed to a combination tre

290、atment with a topoisomerase I inhibitor to treat patients.The second PCT application was filed on April 23,2021,with applications pending in Europe,the United States and 15 other foreign jurisdictions with an expiry no earlier than April 2041.Claims are directed to treatment of patients having gastr

291、ic,esophageal and gastro-esophageal cancer including certain dosing regimens.The third PCT application filed on December 15,2021,with national phase entry due in June 2023,covering treatment of patients having head and neck cancer,including certain dosing regimens.The fourth PCT application was file

292、d on December 16,2021,with national phase entry due in June 2023,covering a pharmaceutical formulation that contains petosemtamab.23 Our patent portfolio related our bispecific antibody candidate MCLA-129 comprises one PCT filed on August 9,2018,with one issued patent in a foreign jurisdiction and w

293、ith applications pending in the United States,Europe and 19 other foreign jurisdictions with an expiry of no earlier than August 2038.Claims are directed to the MCLA-129 composition of matter and methods of using MCLA-129 in the treatment or prevention of various solid tumors.Our patent portfolio re

294、lated our bispecific antibody candidate MCLA-145 comprises one PCT filed on September 22,2017,with two issued patents in a foreign jurisdiction and with applications pending in the United States,Europe and 18 other foreign jurisdictions with an expiry no earlier than September 2037.Claims are direct

295、ed to the MCLA-145 composition of matter and methods of using MCLA-145 in the treatment or prevention of various solid tumors.In addition,our portfolio includes a PCT application filed on December 3,2021,related to dosage regimens and methods of treating patients with certain kinds of solid tumors.O

296、ur patent portfolio related to our MeMo and common light chain transgenic animal consists of seven issued U.S.patents,five pending U.S.applications,three issued European patents that have been validated in many countries,and three pending European applications,21 issued foreign patents and 12 pendin

297、g foreign applications,all with an expected expiry not earlier than June 2029.Claims are directed to a common light chain animal and methods of producing hybridomas,host cells,and antibodies relating to the use of a common light chain and by exposing the animal to an antigen.Our patent portfolio rel

298、ated to efficient dimerization of heavy chains promoting efficient production of multispecific antibodies,binding domains and mixtures of antibodies,methods and host cells for recombinant production thereof,and comprises two PCT applications filed on April 19,2013,which has resulted in seven issued

299、U.S.patents,one pending U.S.application,two issued European patents,two pending European applications,34 issued foreign patents,and eighteen pending foreign applications,all with an expected expiry not earlier than April 2033.Our patent portfolio related to our trispecific antibody technology compri

300、ses one PCT application,filed on March 29,2019,with pending applications in the United States,Europe,and 19 foreign jurisdictions,with an expiry no earlier than March 2039.Claims are directed to,among other things,a multivalent antibody format,including the Triclonics format.Our patent portfolio rel

301、ated to our Spleen to Screen technology consists of four issued U.S.patents,one pending U.S.application,one pending European application and four issued foreign patents,with two foreign pending applications,all with an expected expiry not earlier than September 2032.We plan to continue to expand our

302、 intellectual property estate by filing patent applications directed to dosage forms,methods of treatment and additional compositions created or identified from our Biclonics and Triclonics technology platforms,improvements to those platforms and our ongoing development of our antibody candidates.Sp

303、ecifically,we seek patent protection in the United States and internationally for novel compositions of matter directed to aspects of the molecules,basic structures and processes for manufacturing these molecules and the use of these molecules in a variety of therapies,in combinations,dosages,method

304、s of treatments,among other features.Our patent portfolio is intended to cover,but is not limited to,the composition of matter of our bispecific antibody candidates,their methods of use,the Biclonics and Triclonics technology platforms used to generate them,related technologies and/or other aspects

305、of the inventions that are important to our business,including our MeMo mouse,and common light chain generation platforms and techniques,Spleen to Screen technology,and recombinant host cells capable of producing our antibody candidates,methods of purification,and heterodimerization,among other prop

306、rietary technology.We also rely on trademarks,trade secrets and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to,or that we do not consider appropriate for,patent protection.We also rely on know-how,continuing technological innovation and

307、in-licensing opportunities to develop,strengthen,and maintain our proprietary positions.Our success will depend on our ability to obtain and maintain patent and other proprietary protection for commercially important technology,inventions and know-how related to our business,defend and enforce our p

308、atents,maintain our licenses to use intellectual property owned by third parties,preserve the confidentiality of our trade secrets and operate without infringing valid and enforceable patents and other proprietary rights of third parties.For important factors related to our proprietary technology,in

309、ventions,improvements,platforms and antibody candidates,please see the section entitled“Risk FactorsRisks Related to Intellectual Property and Information Technology.”24 Government RegulationWe are subject to extensive regulation.We expect our antibody candidates to be regulated as biologics.Biologi

310、cal products are subject to regulation under the Federal Food,Drug,and Cosmetic Act(FD&C Act)and the Public Health Service Act(PHS Act)and other federal,state,local and foreign statutes and regulations.Both the FD&C Act and the PHS Act and their corresponding regulations govern,among other things,th

311、e testing,manufacturing,safety,efficacy,labeling,packaging,storage,record keeping,distribution,reporting,advertising and other promotional practices involving biological products.U.S.Biological Products Development ProcessThe process required by the FDA before a biologic may be marketed in the Unite

312、d States generally involves the following:completion of extensive nonclinical,sometimes referred to as pre-clinical laboratory tests,and pre-clinical animal trials and applicable requirements for the humane use of laboratory animals and formulation studies in accordance with applicable regulations,i

313、ncluding good laboratory practices(GLPs);submission to the FDA of an IND,which must become effective before human clinical trials may begin;approval by an institutional review board(IRB)or ethics committee at each clinical site before the trial is commenced;performance of adequate and well-controlle

314、d human clinical trials according to the FDAs regulations,commonly referred to as good clinical practice(GCP),regulations and any additional requirements for the protection of human research subjects and their health information,to establish the safety and efficacy of the proposed biological product

315、 for its intended use;submission to the FDA of a Biologics License Application(BLA)that includes substantive evidence of safety,purity,and potency from results of nonclinical testing and clinical trials;satisfactory completion of an FDA inspection of the manufacturing facility or facilities where th

316、e biological product is produced to assess compliance with current Good Manufacturing Practice(cGMP)requirements to assure that the facilities,methods and controls are adequate to preserve the biological products identity,strength,quality and purity;potential FDA audit of the nonclinical and clinica

317、l trial sites that generated the data in support of the BLA;and FDA review and approval,or licensure,of the BLA.Before testing any antibody candidate in humans,the antibody candidate enters the pre-clinical testing stage.Pre-clinical tests,also referred to as nonclinical trials,generally include lab

318、oratory evaluations of product chemistry,toxicity and formulation,as well as animal studies to assess the potential safety and activity of the antibody candidate.The conduct of the pre-clinical tests must comply with federal regulations and requirements including GLPs.The clinical trial sponsor must

319、 submit the results of the pre-clinical tests,together with manufacturing information,analytical data,any available clinical data or literature and a proposed clinical protocol,to the FDA as part of the IND.Some pre-clinical testing may continue even after the IND is submitted.The IND automatically

320、becomes effective 30 days after receipt by the FDA,unless the FDA places the clinical trial on a clinical hold within that 30-day time period.In such a case,the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.The FDA may also impose clinical holds,at

321、 any time before or during clinical trials due to safety concerns or non-compliance.If the FDA imposes a clinical hold,trials may not recommence without FDA authorization and then only under terms authorized by the FDA.Clinical trials involve the administration of the biological antibody candidate t

322、o healthy volunteers or patients under the supervision of qualified investigators,generally physicians not employed by or under the trial sponsors control.Clinical trials are conducted under protocols detailing,among other things,the objectives of the clinical trial,dosing procedures,subject selecti

323、on and exclusion criteria,and the parameters to be used to monitor subject safety,including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur.Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND.While the IN

324、D is active,progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report,among other information,must be submitted at least annually to the FDA,and written IND safety reports must be submitted to the FDA and investigators for seriou

325、s and unexpected suspected adverse events,findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs,findings from animal or in vitro testing suggesting a significant risk to humans,and any clinically important increased incidence of a serious suspected

326、adverse reaction compared to that listed in the protocol or investigator brochure.Clinical trials must be conducted and monitored in accordance with the FDAs regulations comprising the GCP requirements,including the requirement that all research subjects provide informed consent.Further,each clinica

327、l trial must be reviewed and 25 approved by an independent IRB at or servicing each institution at which the clinical trial will be conducted.An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in t

328、he clinical trials are minimized and are reasonable in relation to anticipated benefits.The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.There a

329、re also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:Phase 1.The biological antibody candidate is initially introduced

330、 into healthy human subjects and tested for safety.In the case of some products for severe or life-threatening diseases,especially when the product may be too inherently toxic to ethically administer to healthy volunteers,the initial human testing is often conducted in patients.Phase 2.The biologica

331、l antibody candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks,to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance,optimal dosage and dosing schedule.Phase 3.Clinical trials ar

332、e undertaken to further evaluate dosage,clinical efficacy,potency,and safety in an expanded patient population at geographically dispersed clinical trial sites.These clinical trials are intended to establish the overall risk/benefit ratio of the product and provide an adequate basis for product labe

333、ling.In some cases,the FDA may require,or sponsors may voluntarily pursue,additional clinical trials after a product is approved to gain more information about the product.In addition,the FDA may require post marketing clinical trials,sometimes referred to as phase 4 clinical trials,designed to further assess a biological products safety and effectiveness,and testing and surveillance programs to m