Means and methods for treating castration-resistant prostate cancer

Abstract

The present invention relates to means and methods for treating castration-resistant prostate cancer. The present invention relates to the field of therapeutic antibodies for use in the treatment of individuals with castration-resistant prostate cancer. More specifically, the present invention relates to the treatment of castration-resistant prostate cancer using a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3. In addition, the present invention relates to the treatment of castration resistant prostate cancer using an antibody comprising an antigen binding site that can bind to an ERBB3 extracellular portion. The invention also relates to the treatment of castration resistant prostate cancer using a combination of one of the antibodies and an androgen receptor axis-targeting agent.

Description

[0001] This application is a divisional application of Chinese patent application filed on August 4, 2023, with application number 202380057774.5 and invention title "Methods and means for treating castration-resistant prostate cancer". Technical Field

[0002] This invention relates to the field of antibodies. Specifically, this invention relates to the field of therapeutic (human) antibodies for treating castration-resistant prostate cancer. More specifically, this invention relates to antibodies binding to ERBB3, and antibodies binding to ERBB2 and ERBB3, and their use in combination therapy or combination therapy with androgen receptor axis-targeting agents to treat cancer. Background Technology

[0003] In 2020, prostate cancer was the second most common malignant tumor among men worldwide and the fifth leading cause of cancer death (Sung et al., "Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries." CA Cancer J Clin 71(3):209-249,2021). In 2021, the estimated number of advanced prostate cancer cases in the United States was approximately 250,000 (Siegel et al., "Cancer Statistics, 2021." CA Cancer J Clin 71(1):7-33, 2021), including a subgroup of 30,000 men with castration-resistant prostate cancer (CRPC) (Scher et al., Prostate Cancer ClinicalTrialsWorking (2016). "Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer ClinicalTrialsWorking Group 3." J Clin Oncol 34(12):1402-1418, 2015). For patients with locally advanced, recurrent, or metastatic tumors, current treatment goals include prolonging survival and progression-free interval while maintaining a good quality of life.

[0004] The primary treatment for men with metastatic prostate cancer since the 1940s has been androgen deprivation therapy (ADT) alone, using surgical or chemical castration to suppress the production of testosterone. Chemotherapy is usually initiated only after patients have stopped responding to ADT alone, at which point the disease is considered castration-resistant.

[0005] The androgen receptor (AR) is a lineage survival factor for luminal cancer cells in prostate tumors and plays an important role in cancer. ADT remains the mainstay of treatment for advanced / metastatic disease that targets AR signaling. Next-generation AR signaling inhibitors currently approved for use in one treatment include abiraterone and enzalutamide (Swami et al., 2020, "Advanced Prostate Cancer: Treatment Advances and Future Directions." Trends Cancer 6(8):702-715). These inhibitors are able to more strongly block the androgen receptor (AR) axis, prolonging the survival of men with CRPC. However, the degree of survival improvement remains insufficient, and most patients eventually develop resistance to these new drugs. Resistance mechanisms to next-generation hormonal drugs are complex, possibly dependent or independent of AR signaling, and the AR axis can still be an important driver of advanced / metastatic CRPC after progression (Verma et al., 2020, Resistance to second-generation antiandrogens in prostate cancer: pathways and mechanisms." Cancer Drug Resist 3(4):742-761).

[0006] Although preclinical studies have suggested that the ERBB signaling pathway is involved in the progression of CRPC (Craft et al., 1999. A mechanism for hormone independent prostate cancer through modulation of androgen receptor signaling by the HER-2 / neu tyrosine kinase. Nat Med 5(3):280-285), successful targeting of this pathway has not been achieved in the clinical setting, failing to demonstrate antitumor activity of ERBB2-targeting drugs, including trastuzumab and afatinib (Ziada et al., 2004, The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial. Prostate 60(4):332-337. Molife et al., 2014, Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer. Future Oncol 10(2):219-231.).

[0007] More than 30,000 patients with metastatic CRPC (mCRPC) are currently receiving one or two systemic therapies, but the disease invariably progresses, requiring subsequent treatment. Thus, the medical need for additional treatment options for patients whose disease progresses on AR signaling inhibitor therapy is clearly unmet. In addition, an increasing number of non-metastatic prostate cancer patients currently receiving AR signaling inhibitor therapy will progress, thus increasing the number of patients with AR signaling inhibitor post-CRPC.

[0008] Therefore, there is a need in the art for therapies for castration-resistant prostate cancer. SUMMARY

[0009] The invention provides a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual. The method comprises administering to the individual an effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3. Optionally, the method of treatment further comprises use of an androgen receptor axis-targeting agent.

[0010] The invention provides a method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3. Optionally, the method comprises screening an individual having castration-resistant prostate cancer or an individual suspected of having castration-resistant prostate cancer prior to treating the castration-resistant prostate cancer.

[0011] The invention provides an antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual. The method comprises administering to the individual an effective amount of an antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB3. Optionally, the method of treatment further comprises use of an androgen receptor axis-targeting agent. Optionally, the antibody is a monospecific antibody.

[0012] The invention provides a method of treating castration-resistant prostate cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB3. Optionally, the method comprises screening an individual having castration-resistant prostate cancer or an individual suspected of having castration-resistant prostate cancer prior to treating the castration-resistant prostate cancer. Optionally, the antibody is a monospecific antibody.

[0013] Optionally, the method of treatment further comprises screening a patient suspected of having castration-resistant prostate cancer according to certain inclusion and exclusion criteria.

[0014] Optionally, the method of treatment further comprises administering to the individual an androgen receptor axis-targeting agent.

[0015] The invention provides use of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3 for the manufacture of a medicament for treating castration-resistant prostate cancer in an individual. Optionally, the method or use further comprises use of an androgen receptor axis-targeting agent.

[0016] Optionally, the castration-resistant prostate cancer has progressed after prior cancer treatment with an androgen receptor axis-targeting agent. Optionally, the castration-resistant prostate cancer has progressed after prior treatment with an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, or after prior treatment with an androgen synthesis inhibitor, such as abiraterone acetate. Optionally, the castration-resistant prostate cancer has progressed after prior treatment with enzalutamide.

[0017] Optionally, the method of treatment comprising the use or administration of the bispecific antibody of the application further comprises the use or administration of an androgen receptor axis-targeting agent. Optionally, the bispecific antibody and the androgen receptor axis-targeting agent are administered within the same treatment period. The treatment period typically comprises a cycle of 28 days, during which the bispecific antibody is administered twice, typically on day 1 and day 15 of the cycle (i.e. Q2W), and the androgen receptor axis-targeting agent is administered every day of the cycle (i.e. QD). The administration of the bispecific antibody and / or the androgen receptor axis-targeting agent is continued until a decision to stop treatment is made, but as long as it is deemed clinically relevant or as long as a clinically relevant effect is observed.

[0018] Thus, optionally, the cancer has progressed after prior treatment with an androgen receptor axis-targeting agent. Optionally, if the cancer has progressed after prior treatment with an androgen receptor antagonist, the use of the bispecific antibody in the method of treatment of the application further comprises the use of an androgen receptor antagonist. Optionally, if the cancer has progressed after prior treatment with an androgen receptor antagonist, the method of treatment using the bispecific antibody according to the application further comprises the administration of an androgen receptor antagonist. It is thus envisaged a combination use, wherein a bispecific antibody comprising an antigen-binding site that can bind to an extracellular part of ERBB2 and an antigen-binding site that can bind to an extracellular part of ERBB3 is used together with an androgen receptor antagonist in the same treatment period.

[0019] Thus, the application optionally provides a combination therapy comprising a first container containing an antibody as described herein and a second container containing an androgen receptor axis-targeting agent. The two components can be formulated as separate pharmaceutical compositions (e.g. as a kit-of-parts) and can be administered simultaneously, separately or in any order. As will be appreciated by the skilled person, the two components can be provided at different times during the same treatment cycle. Optionally, a treatment cycle consists of 28 days. Optionally, the bispecific antibody of the application is administered twice (e.g. Q2W) during the treatment cycle and the androgen receptor axis-targeting agent is administered every day during the treatment cycle.

[0020] Optionally, the androgen receptor antagonist used in the previous cancer treatment is the same as the androgen receptor antagonist used in the treatment method of the present invention in combination with the bispecific antibody. Optionally, the androgen receptor antagonist used in the previous cancer treatment and used in combination with the bispecific antibody of the present invention is enzalutamide. Thus, optionally, the present invention provides a combination treatment or combination therapy in which the bispecific antibody comprises an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3, such as Zenocutuzumab, for use with an androgen receptor antagonist, such as enzalutamide.

[0021] Optionally, the enzalutamide is administered at a daily dose of 160 mg.

[0022] Optionally, the cancer has progressed after previous treatment with an androgen synthesis inhibitor. Optionally, if the cancer has progressed after previous treatment with an androgen synthesis inhibitor, the use of the bispecific antibody in the treatment method of the present invention further comprises the use of an androgen synthesis inhibitor. Optionally, if the cancer has progressed after previous treatment with an androgen synthesis inhibitor, the treatment method of the present invention using the bispecific antibody further comprises the administration of an androgen synthesis inhibitor. Thus, a combination use is envisaged in which the bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3 is used together with an androgen synthesis inhibitor during the same treatment period.

[0023] Optionally, the androgen synthesis inhibitor used in the previous cancer treatment is the same as the androgen synthesis inhibitor used in the treatment method of the present invention in combination with the bispecific antibody. Optionally, the androgen synthesis inhibitor used in the previous cancer treatment and used in combination with the bispecific antibody of the present invention is abiraterone acetate, such as Thus, optionally, the present invention provides a combination treatment or combination therapy in which the bispecific antibody comprises an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3, such as Zenocutuzumab, for use with an androgen synthesis inhibitor, for example abiraterone acetate, such as ) during the same treatment period.

[0024] Optionally, the abiraterone acetate, such as is administered at a daily dose of 1000 mg. Optionally, the abiraterone acetate is used in combination with prednisone at 5 mg administered orally twice daily.

[0025] Optionally, the bispecific antibody of the application is administered or used in an amount of 750 mg once every two weeks. Optionally, the bispecific antibody is Zenocutuzumab.

[0026] Optionally, the antibody of the application comprises an antigen binding site that can bind to an extracellular portion of ERBB3 that blocks ERBB3 and its ligand heregulin. Optionally, the antibody binds to domain III of ERBB3. Optionally, the antibody also comprises an antigen binding site that can bind to an extracellular portion of ERBB2. Optionally, the antibody comprises an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the antibody is a bispecific antibody. Optionally, the bispecific antibody of the application comprises a first antigen binding site that can bind to an extracellular portion of ERBB2 and a second antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the bispecific antibody has a first antigen binding site that can bind to domain I of ERBB2 and a second antigen binding site that can bind to domain III of ERBB3. Optionally, the first antigen binding site has a lower affinity for ERBB2 than the second antigen binding site has for ERBB3. Optionally, the antibody is or comprises Zenocutuzumab.

[0027] Optionally, the application provides a method of treatment as disclosed herein, wherein an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3 is used. Optionally, the antibody is a monospecific antibody.

[0028] Optionally, the application provides a method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the antibody comprises an antigen binding site that can bind to domain III of ERBB3.

[0029] Optionally, the application provides a use of an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3 for the manufacture of a medicament for treating castration-resistant prostate cancer in an individual. Optionally, the antibody comprises an antigen binding site that can bind to domain III of ERBB3.

[0030] Optionally, the antibodies of the application, including but not limited to bispecific antibodies, comprise an antigen binding site that can bind to an extracellular portion of ERBB3 that blocks ERBB3 and its ligand heregulin. Optionally, the antibodies also comprise an antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the antibodies comprise an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the antibodies are or comprise Zenocutuzumab.

[0031] Also provided is a method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3 or for treatment with an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the individual for the treatment if the sample does not exhibit a PTEN deletion.

[0032] Also provided is a method of establishing whether an individual having castration-resistant prostate cancer is likely to respond to treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3 or to treatment with an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the sample that does not exhibit a PTEN deletion, thereby establishing that the individual from which the sample was derived is likely to respond to the treatment.

[0033] Also provided is a method of classifying an individual having castration-resistant prostate cancer based on the PTEN status prior to treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3 or prior to treatment with an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) classifying the individual from which the sample was derived as eligible for the treatment if the sample does not exhibit a PTEN deletion.

[0034] Also provided is a method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3 or for treatment with an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the individual for the treatment if the sample exhibits a PTEN deletion.

[0035] Also provided is a method of establishing whether an individual having castration-resistant prostate cancer is likely to respond to treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3 or to treatment with an antibody comprising an antigen binding site that can bind to an extracellular part of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting a sample that exhibits a loss of PTEN, thereby establishing that the individual from which the sample was derived is likely to respond to said treatment.

[0036] Also provided is a method of classifying an individual having castration-resistant prostate cancer based on the PTEN status prior to treatment with a bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3 or treatment with an antibody comprising an antigen binding site that can bind to an extracellular part of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) classifying the individual from which the sample was derived as eligible for said treatment if the sample exhibits a loss of PTEN.

[0037] Optionally, the individual is a human individual. The human individual has castration-resistant prostate cancer or is at risk of developing such disease. Optionally, the individual has metastatic castration-resistant prostate cancer or is at risk of developing metastatic castration-resistant prostate cancer. Thus, the individual is in need of treatment for castration-resistant prostate cancer or metastatic castration-resistant prostate cancer. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 The following amino acid sequences are listed: Figure 1 a: amino acid sequence of the common light chain variable region (VL+CL sequence); Figure 1 b: DNA sequence of the common light chain variable region and its translation (IGKV1-39 / jk1), Figure 1 c: DNA sequence and translation of the common light chain constant region, Figure 1 d: translation of the IGKV1-39 / jk5 common light chain variable region, Figure 1 e: V-region IGKV1-39A; Figure 1 f: common light chain CDR1, CDR2 and CDR3 sequences, all according to IMGT.

[0039] Figure 2 The following IgG heavy chain sequences are listed for use in the production of the bispecific molecule. Figure 2 a: CH1 region, Figure 2 b: hinge region, Figure 2 c: CH2 region, Figure 2d: CH3 domain comprising variants L351K and T366K (KK), Figure 2 e: CH3 domain comprising variants L351D and L368E (DE).

[0040] Figure 3 Nucleic acid and amino acid sequences of variable regions heavy chains are listed. CDR1, CDR2 and CDR3 sequences of each heavy chain variable region according to the Kabat numbering system are also provided. Figure 3 a: heavy chain that binds to ERBB2, Figure 3 b: heavy chain that binds to ERBB3. DETAILED DESCRIPTION

[0041] A subset of CRPC patients develops primary resistance, and eventually almost all patients develop resistance. The development of CRPC resistance is thought to be a subclonal phenomenon, and although resistant clones arise, a subset of tumor cells remains sensitive to androgen deprivation therapy. Without being bound by theory, the inventors recognize that preventing paracrine activation of NRG1 / ERBB3 signaling to attenuate drivers of antiandrogen resistance in CRPC is an option that would use an antibody comprising an antigen binding site that can bind to domain III of the extracellular portion of ERBB3, or an antibody comprising an antigen binding site that can bind to domain III of the extracellular portion of ERBB3 and an antigen binding site that can bind to domain I of the extracellular portion of ERBB2, as described herein, in a method of treating a castration-resistant prostate cancer in an individual.

[0042] The tyrosine kinase transmembrane receptors ERBB family is also known as the human epidermal growth factor (EGF) receptor family (HER). This family has four members: ERBB (erythroblastic leukemia)-1, ERBB2, ERBB3, and ERBB4. These receptors (reviewed in Yarden and Pines 2012) are widely expressed in epithelial cells. Upregulation of HER receptors or their ligands, such as neuregulin (NRG) (also known as heregulin (HRG)) or epidermal growth factor (EGF)), is a common event in human cancers (Wilson, Timothy R, et al. Nature 487, 7408 (2012): 505-9). Overexpression of ERBB1 and ERBB2 occurs particularly in epithelial tumors and is associated with tumor invasion, metastasis, chemotherapy resistance, and poor prognosis (Zhang, Hongtao, et al. The Journal of clinical investigation 117, 8 (2007): 2051-8). In normal breast, ERBB3 has been shown to be important for the growth and differentiation of luminal epithelium. For example, loss / inhibition of ERBB3 leads to selective expansion of basal cells over luminal epithelial cells (Balko, Justin M, et al. Proceedings of the National Academy of Sciences 109, 1 (2012): 221-6). Binding of ligands to the extracellular domains of RTKs induces receptor dimerization, which occurs between the same (homo-dimerization) and different (hetero-dimerization) receptor subtypes. Dimerization activates the intracellular tyrosine kinase domains, which undergo autophosphorylation, which in turn can activate a number of downstream pro-proliferative signaling pathways, including those mediated by mitogen-activated protein kinase (MAPK) and the pro-survival pathway Akt (reviewed in Yarden, Yosef, and Gur Pines. Nature reviews. Cancer 12, 8 553-63). No specific endogenous ligand for ERBB2 has been identified, so it is assumed that it usually signals through hetero-dimerization (Sergina, Natalia V, et al. Nature 445, 7126 (2007): 437-41). ERBB3 can be activated by binding to its ligands. These include, but are not limited to, neuregulin (NRG) (also known as heregulin (HRG)).

[0043] ERBB1 is known by a variety of synonyms, the most common of which is EGFR. EGFR has an extracellular domain (ECD) that is composed of four subdomains, two of which are involved in ligand binding and two of which are involved in homodimerization and heterodimerization. EGFR integrates extracellular signals from a variety of ligands to produce different intracellular responses. EGFR has been implicated in a number of human epithelial malignancies, notably breast, bladder, non-small cell lung, lung, colon, ovarian head and neck, and brain cancers. Activating mutations in this gene, as well as overexpression of the receptor and its ligands, have been found to produce an autocrine activation loop. Such receptor tyrosine kinases (RTKs) have been widely used as targets for cancer therapy. Both small molecule inhibitors against RTKs and monoclonal antibodies (mAbs) against the extracellular ligand binding domain (monospecific bivalent) have been developed, and have had several successes in the clinic to date. The database accession number for the human EGFR protein and its encoding gene is (GenBank NM_005228.3). This accession number is provided primarily to provide a means of further identifying the EGFR protein as a target, while the actual sequence of the EGFR protein to which the antibody binds can vary, for example due to mutations in the encoding gene, such as occur in some cancers or similar situations.

[0044] The term "ERBB2" as used herein refers to the protein in humans that is encoded by the ERBB2 gene. Alternative names for this gene or protein include: CD340; HER2; HER-2 / neu; MLN 19; NEU; NGL; TKR1. The ERBB2 gene is commonly referred to as HER2 (from human epidermal growth factor receptor 2). When ERBB2 is referred to herein, the reference is to the human ERBB2. Antibodies comprising an ERBB2 antigen binding site bind to human ERBB2. Due to sequence and tertiary structure similarity between humans and other mammalian orthologs, an ERBB2 antigen binding site can also bind to such orthologs, but not necessarily so. The database accession numbers for the human ERBB2 protein and its encoding gene are (NP_001005862.1, NP_004439.2 NC_000017.10 NT_010783.15 NC_018928.2). This accession number is provided primarily to provide a means of further identifying the ERBB2 protein as a target, while the actual sequence of the ERBB2 protein to which the antibody binds can vary, for example due to mutations in the encoding gene, such as occur in some cancers or similar situations. An ERBB2 antigen binding site binds to ERBB2 and to a variety of variants thereof, such as are expressed by some ERBB2-positive tumor cells. An antigen binding site that binds to ERBB2 preferably binds to domain I of ERBB2.

[0045] As used herein, the term "ERBB3" refers to the protein in humans that is encoded by the ERBB3 gene. Alternative names for this gene or protein include: HER3; LCCS2; MDA-BF-1; c-ERBB3; c-ERBB3; ERBB3-S; p180-ERBB3; p45-sERBB3; and p85-sERBB3. When reference is made herein to ERBB3, the reference is to human ERBB3. Antibodies comprising an ERBB3 antigen binding site bind human ERBB3. Due to sequence and tertiary structure similarity between human and other mammalian orthologs, an ERBB3 antigen binding site can also bind such orthologs, but not necessarily so. The database accession numbers for the human ERBB3 protein and its encoding gene are NP_001973.2 and NC_000012.11, which includes the genomic location of the ERBB3 gene on chromosome 12 (56473892 to 56497289). This accession number is provided primarily to provide a means of further identifying the ERBB3 protein as the target, while the actual sequence of the ERBB3 protein bound by the antibody can vary, for example due to mutations in the encoding gene, such as occur in some cancers or the like. An ERBB3 antigen binding site binds to ERBB3 and to various variants thereof, such as are expressed by some ERBB3-positive tumor cells. An antigen binding site that binds ERBB3 preferably binds to domain III of ERBB3.

[0046] When reference is made to ERBB1, ERBB2, or ERBB3, or alternative names thereof, the reference is to human ERBB1, ERBB2, or ERBB3. Antibodies referred to herein bind to ERBB1, ERBB2, or ERBB3, and to many mutant ERBB1, ERBB2, or ERBB3 proteins, as can be found in cancers.

[0047] The present application provides a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual. The method comprises administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3. Optionally, the method of treatment also comprises the use of an androgen receptor axis-targeting agent.

[0048] The present disclosure provides a method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3. Optionally, the method comprises screening an individual having castration-resistant prostate cancer or an individual suspected of having castration-resistant prostate cancer for treatment of castration-resistant prostate cancer. Optionally, the method of treatment further comprises administering to the individual an androgen receptor axis-targeting agent.

[0049] The present disclosure provides use of a bispecific antibody comprising an antigen-binding site that binds or can bind to an extracellular portion of ERBB2 and an antigen-binding site that binds or can bind to an extracellular portion of ERBB3 for the manufacture of a medicament for treating castration-resistant prostate cancer in an individual. Optionally, the treatment or use further comprises use of an androgen receptor axis-targeting agent.

[0050] Endocrine and metabolic outcomes represent major side effects associated with the safety of hormone therapy for prostate cancer. For example, abiraterone acetate treatment can lead to hyperaldosteronism, hypokalemia, hypertension, elevated liver function tests, insulin resistance, and hyperglycemia. Enzalutamide is known to induce or exacerbate hypertension and is associated with an increase in falls and fractures in elderly patients. Thus, the safety concerns associated with abiraterone acetate and enzalutamide are expected to have limited overlap with zanohumab, and the well-tolerated safety profile of zanohumab makes it an excellent candidate for combination therapy in this elderly, heavily pretreated patient population. Continued blockade of CRPC using AR signaling inhibitors, while blocking the HER3 / NRG1 resistance signaling pathway, can treat patients after failure of next-generation AR drugs. The use of androgen-targeting agents to continue treatment of CRPC, while using an antibody comprising an antigen-binding site that can bind to domain III of an extracellular portion of ERBB3, or an antibody comprising an antigen-binding site that can bind to domain III of an extracellular portion of ERBB3 and an antigen-binding site that can bind to domain I of an extracellular portion of ERBB2, is disclosed herein for use in a method of treating castration-resistant prostate cancer in an individual.

[0051] Optionally, the castration-resistant prostate cancer has progressed after a previous cancer treatment. Such previous treatment, also referred to as anticancer therapy or treatment, optionally comprises an androgen receptor axis-targeting agent. Optionally, the cancer has progressed after previous treatment with an androgen receptor antagonist, such as a second-generation androgen receptor antagonist. Optionally, the cancer has progressed after previous treatment with a first-generation androgen receptor antagonist, such as flutamide, bicalutamide or nilutamide, or a second-generation androgen receptor antagonist, such as apalutamide, darolutamide or enzalutamide, or an androgen receptor antagonist known to the person of ordinary skill in the art, such as proxalutamide, BMS-641988, TQB3720, SHR3680 or TRC-253. Optionally, the cancer has progressed after previous treatment with enzalutamide.

[0052] Optionally, the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0053] Optionally, the method of treatment comprising the use or administration of the bispecific antibody of the application further comprises the use or administration of an androgen receptor axis-targeting agent.

[0054] Thus, optionally, the cancer has progressed after previous treatment with an androgen receptor axis-targeting agent. Optionally, if the cancer has progressed after previous treatment with an androgen receptor antagonist, the use of the bispecific antibody in the method of treatment according to the application further comprises the use of an androgen receptor antagonist. Optionally, if the cancer has progressed after previous treatment with an androgen receptor antagonist, the method of treatment with the bispecific antibody according to the content of the application further comprises the administration of an androgen receptor antagonist. It is thus envisaged a combined use, wherein the bispecific antibody comprising an antigen-binding site that can bind to an extracellular part of ERBB2 and an antigen-binding site that can bind to an extracellular part of ERBB3 can be used together with an androgen receptor antagonist during the same treatment period. Thus, optionally, the cancer has progressed after previous treatment with an androgen receptor antagonist, and the method of treatment with the antibody further comprises the use of an androgen receptor antagonist.

[0055] Optionally, the androgen receptor antagonist used in the prior cancer treatment is the same as the androgen receptor antagonist used in the method of treatment of the present application in combination with the bispecific antibody of the present application. Optionally, the androgen receptor antagonist used in the prior cancer treatment and used in combination with the bispecific antibody of the present application is apalutamide, darolutamide or enzalutamide. Optionally, the androgen receptor antagonist used in the prior cancer treatment and used in combination with the antibody of the present application is enzalutamide. Thus, optionally, the present application provides a combination treatment or combination therapy in which the bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3, such as zanlibotamab, is used in combination with an androgen receptor antagonist, such as enzalutamide.

[0056] Optionally, the antibody of the present application is combined with an androgen receptor antagonist including flutamide, bicalutamide nilutamide, a second generation androgen receptor antagonist such as apalutamide, darolutamide or enzalutamide, or an androgen receptor antagonist known to one of ordinary skill in the art such as proxalutamide, BMS-641988, TQB3720, SHR3680 or TRC-253.

[0057] Optionally, enzalutamide is administered at a daily dose of 160 mg. Optionally, enzalutamide is administered at a daily dose of 160 mg and the bispecific antibody of the present application is administered at an amount of 750 mg once every two weeks. Optionally, the bispecific antibody is zanlibotamab. Thus, the treatment of the individual comprises administration of both enzalutamide and zanlibotamab. Optionally, the enzalutamide used in the prior cancer treatment and further comprised in the method of treatment of the present application is administered at a daily dose of 160 mg.

[0058] Optionally, the cancer has progressed after prior treatment with an androgen synthesis inhibitor. Optionally, the use of the bispecific antibody in the method of treatment according to the application further comprises the use of an androgen synthesis inhibitor if the cancer has progressed after prior treatment with an androgen synthesis inhibitor. Optionally, the method of treatment using the bispecific antibody according to the application further comprises the administration of an androgen synthesis inhibitor if the cancer has progressed after prior treatment with an androgen synthesis inhibitor. It is thus envisaged a combination use wherein the bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3 is used together with an androgen synthesis inhibitor during the same treatment period. Thus, optionally, the cancer has progressed after prior treatment with an androgen synthesis inhibitor and the method of treatment with the antibody further comprises the use of an androgen synthesis inhibitor.

[0059] Optionally, the androgen synthesis inhibitor used in the prior cancer treatment is the same as the androgen synthesis inhibitor used in the method of treatment with the bispecific antibody according to the application. Optionally, the androgen synthesis inhibitor used in the prior cancer treatment is the same as the androgen synthesis inhibitor used in the method of treatment with the bispecific antibody according to the application is abiraterone acetate, such as Thus, optionally, the present application provides a combination treatment or combination therapy wherein the bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3, such as zanu-tumab, is used together with an androgen synthesis inhibitor, such as abiraterone acetate, e.g. ) during the same treatment period.

[0060] Optionally, the antibody according to the application is combined with an androgen synthesis inhibitor, such as abiraterone acetate. Optionally, the antibody is a bispecific antibody as disclosed herein. Optionally, the abiraterone acetate used in the prior cancer treatment and further comprised in the method of treatment according to the application is administered at a daily dose of 1000 mg.

[0061] Optionally, the abiraterone acetate, such as is administered at a daily dose of 1000 mg. Optionally, the abiraterone acetate is used in combination with 5 mg prednisone administered orally twice daily. Optionally, the abiraterone acetate is administered at a daily dose of 1000 mg, such as and the bispecific antibody according to the application is administered once every two weeks in an amount of 750 mg. Optionally, the bispecific antibody is zanu-tumab. Thus, the treatment of the individual comprises the administration of both abiraterone acetate and zanu-tumab during the same treatment period.

[0062] Additionally, the individual can have received other prior treatment for prostate cancer, including taxane-based chemotherapy, such as docetaxel or cabazitaxel. Additionally or alternatively, the individual can have also received prior treatment with sipuleucel-T or radiopharmaceuticals, such as radium 223 or lutetium 177.

[0063] Radiopharmaceuticals or medical radioisotopes are a group of drugs that contain a radioisotope. Examples include radium 223 and lutetium (177Lu) oxo- peptide. Lutetium (177Lu) oxo- peptide (international nonproprietary name or INN) or 177 Lu DOTA-TATE, trade name is a chelated complex of the lutetium element radioisotope with DOTA-TATE for peptide receptor radionuclide therapy.

[0064] The terms "individual" and "patient" are used interchangeably herein to refer to a mammal, such as a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, monkey, cow, horse, pig, and the like (e.g., a patient having cancer, such as a human patient). Alternatively, the individual is a human individual. In this context, the individual has castration-resistant prostate cancer, or is at risk of developing castration-resistant prostate cancer.

[0065] As used herein, castration-resistant prostate cancer (CRPC) refers to an individual having prostate cancer that has worsened after a previous prostate treatment, and whose testosterone level is equal to or lower than the level detected after the individual was castrated (also referred to as "castration level of testosterone"). Alternatively, the individual exhibits an increase in serum prostate specific antigen while receiving androgen deprivation therapy (ADT), and / or new metastases have occurred and / or existing metastases have worsened. Alternatively, the individual having CRPC has a serum testosterone level of < 50 ng / dL.

[0066] Castration is used to suppress the production of androgens, such as testosterone, which is one approach to treat prostate cancer to reduce circulating androgen levels. Castration is typically achieved by surgery (orchiectomy) or chemically. Such chemical means include androgen deprivation therapy (ADT), chemotherapy (including but not limited to docetaxel or cabazitaxel ), androgen receptor axis-targeted (ARAT) agents, androgen synthesis inhibitors, and (second generation) androgen receptor antagonists. Examples include but are not limited to abiraterone, enzalutamide, apalutamide, and darolutamide. Further examples of AR antagonists are included in Table 1.

[0067] Table 1. Developmental history of AR antagonists for prostate cancer

[0068]

[0069] Optionally, the castration-resistant prostate cancer is cancer following a series of second-generation hormonal agents for the treatment of castration-resistant prostate cancer. Optionally, the castration-resistant prostate cancer is cancer that has progressed following the administration of no more than two second-generation hormonal agents for the treatment of castration-resistant prostate cancer. Such second-generation hormonal agents include, but are not limited to, androgen receptor antagonists (including, but not limited to, enzalutamide) or androgen synthesis inhibitors (including, but not limited to, abiraterone).

[0070] Optionally, the individual to be treated exhibits an increase in prostate specific antigen (PSA) levels defined as two increases to a minimum of >1 ng / mL of PSA prior to the initiation of treatment. Optionally, the increase is over a previous reference value. An increase in prostate specific antigen (PSA) levels generally refers to an increase in PSA of more than 25% and greater than 2 ng / ml above nadir confirmed by progression at two time points separated by at least three weeks.

[0071] Optionally, the patient can have discontinued administration of an androgen receptor axis-targeting agent (such as abiraterone or enzalutamide) for more than 14 days prior to recording an increase in PSA levels upon resumption of administration of the agent.

[0072] The term "androgen receptor axis-targeting agent" herein includes androgen synthesis inhibitors and androgen receptor antagonists. Thus, an androgen receptor axis-targeting agent as referred to herein prevents, blocks or reduces the signaling activity of the androgen receptor. Activity of the androgen receptor axis is involved in the progression of castration-resistant prostate cancer. The effect on the androgen receptor axis can be achieved using an androgen synthesis inhibitor (such as abiraterone) which affects serum androgen levels (such as testosterone) such that androgen receptor activity is prevented, blocked or reduced. Alternatively, the effect on the androgen receptor axis can be achieved using an androgen receptor antagonist such as enzalutamide to prevent, block or reduce the binding of ligands to the androgen receptor and its activation.

[0073] At the start of treatment, at least one of the following inclusion factors IF1-IF7, more than one or all are applicable to the individual to be treated. Optionally, the individual includes or meets all of the inclusion factors IF1-IF7.

[0074] IF1. Age equal to or greater than 18 years.

[0075] IF2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0076] IF3. Life expectancy of 12 weeks or more.

[0077] IF4. At least three weeks since any major surgery, completion of radiation therapy, completion of all prior systemic anticancer therapy, or if prior therapy was a single agent small molecule therapeutic, at least 5 half-lives, and fully recovered from acute toxicities of any prior therapy, to National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 Grade equal to or less than 1, with the exception of alopecia or neuropathy. Such single agent small molecule therapeutics can be flutamide, ketoconazole, and the like.

[0078] IF5. Left ventricular ejection fraction (LVEF) of equal to or greater than 50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA).

[0079] IF6. Adequate organ function, depending on:

[0080] IF6.1. Absolute neutrophil count of equal to or greater than 1.5 x 10 9 / L.

[0081] IF6.2. Hemoglobin level of equal to or greater than 9 g / dL.

[0082] IF6.3. Platelet count of equal to or greater than 100 x 10 9 / L.

[0083] IF6.4. Serum calcium within normal range (or corrected with supplementation).

[0084] IF6.5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of equal to or less than 2.5 x upper limit of normal (ULN), but if liver malignancy is involved, ALT / AST of equal to or less than 5 x ULN.

[0085] IF6.6. Total bilirubin level of equal to or less than 1.5 x ULN, but with the proviso that total bilirubin of equal to or less than 3 x ULN in the case of Gilbert's disease.

[0086] IF6.7. Estimated glomerular filtration rate of more than 30 mL / min according to the Cockroft-Gault formula, and

[0087] IF6.8. Serum albumin of more than 3.0 g / dL.

[0088] IF7. Having a formalin-fixed paraffin-embedded (FFPE) tumor specimen. The specimen can be collected from the outset as an archival FFPE tumor sample, preferably collected within 2 years after the start of treatment.

[0089] Optionally, all values of the organ function measurements according to IF6 have an upper limit observed in healthy individuals.

[0090] Optionally, the individual to be treated comprises one or more factors selected from the group consisting of IF1 -IF7. Optionally, the individual to be treated comprises factors IF2, IF3, IF5 and IF6. Optionally, the individual to be treated comprises all factors IF1 -IF7.

[0091] Herein, the ECOG performance status score grades are defined as follows: 0: Fully active, able to carry on all pre-disease performance without restriction. 1 : Limited in physically strenuous activity but ambulatory, able to carry out work of a light or sedentary nature, such as light housekeeping, office work. 2: Ambulatory and capable of self-care, but unable to perform any work activities. Up to 50% of waking hours are spent in bed or chair. 3: Capable of only limited self-care, more than 50% of waking hours spent in bed or chair. 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5: Dead.

[0092] Optionally, the individual to be treated has histologically confirmed prostate adenocarcinoma, optionally without neuroendocrine differentiation or small cell features.

[0093] Optionally, the individual to be treated has metastatic disease, documented by at least 2 bone lesions on whole body bone scan, or soft tissue disease documented by computed tomography (CT) scan / magnetic resonance imaging (MRI).

[0094] Optionally, the individual to be treated has a serum testosterone level of < 1.73 nmol / L (< 50 ng / dL) prior to the start of treatment. Optionally, the individual to be treated is receiving androgen deprivation therapy. Optionally, the individual to be treated is receiving androgen deprivation therapy and has a serum testosterone level of < 1.73 nmol / L (< 50 ng / dL) prior to treatment. Thus, optionally, the step of determining the serum testosterone level of a sample obtained from the individual prior to the method of treatment. Thereafter, the individual can be selected for treatment if the serum testosterone level is < 1.73 nmol / L (< 50 ng / dL). The PCWG3 guidelines recommend the use of a testosterone assay with a sensitivity of 1 to 2 ng / dL for the determination of serum testosterone levels, and such assays are readily available.

[0095] Optionally, the prior treatment with an androgen receptor axis-targeting agent is initiated at least 90 days or at least 118 days prior to the initiation of the treatment of the application. A maximum of 30 days of interruption of dosing is allowed within the at least 90 or 118 days.

[0096] Optionally, the individual to be treated has CRPC or CRPC disease progression according to the Prostate Cancer Working Group 3 (PCWG3) criteria. Optionally, the CRPC disease progression is established according to at least one or more of the following criteria:

[0097] 1. An increase in prostate specific antigen (PSA) level defined as two consecutive increases in PSA from a prior reference value, reaching a minimum of >1 ng / mL prior to the initiation of treatment, provided that an increase in PSA level is documented after resumption of use of an androgen receptor axis-targeting agent (such as abiraterone or enzalutamide) if the patient has had an interruption of dosing of the agent for more than 14 days.

[0098] 2. Soft tissue disease progression defined by RECIST vl. l.

[0099] 3. Progression of previously normal (<10 mm) lymph nodes, determined by short axis growth of >5 mm.

[0100] 4. Bone disease progression defined by two or more new lesions on a whole body bone scan.

[0101] An increase in prostate specific antigen (PSA) or the level at which the increase is determined is an increase in PSA greater than 25% and above nadir >2 ng / ml, confirmed by progression at two time points separated by at least three weeks. (See Scher et al., 2016, Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3." J Clin Oncol 34(12): 1402-1418.).

[0102] Optionally, the individual to be treated is receiving a stable dose of bisphosphonate or denosumab for a period of at least 4 weeks. The bisphosphonate or denosumab can be provided for maintenance or improvement of bone health.

[0103] Optionally, the individual to be treated is able to swallow oral medications and does not have a gastrointestinal condition that is considered to compromise intestinal absorption (e.g., malabsorption, resection).

[0104] Optionally, a premedication with the following substances is provided:

[0105] - Aracetamol / Acetaminophen 1000 mg PO or IV.

[0106] - Dexchlorpheniramine 5 mg IV (or other anti-Hl equivalent, PO or IV) - Dexamethasone 10 mg IV (or equivalent, PO or IV). If needed, a corticosteroid can be administered prior to Day 1 of Cycle 1 and should be used for subsequent injections at the investigator's discretion to manage infusion-related reactions (IRRs).

[0107] - H2 antagonists can be given at the investigator's discretion.

[0108] Optionally, the individual to be treated has not received more than two second-generation hormonal agents for metastatic disease. Such agents include abiraterone and enzalutamide. Optionally, the individual to be treated has not received more than two systemic chemotherapy for metastatic disease. Such chemotherapies include docetaxel and cabazitaxel Optionally, the individual to be treated has not previously received anti-HER3-directed therapy.

[0109] Optionally, the individual shows clinical efficacy following treatment with an anti-CRPC according to the present application according to PCWG3-modified RECIST vl. l criteria. Optionally, the patient exhibits progression-free survival (PFS), non-progression of disease (Non-PD), no evidence of disease (NED), stable disease (SD), partial response (PR), or complete response (CR) according to PCWG3-modified RECIST vl. l criteria. Optionally, the patient exhibits disease control in radiographically measurable lymph node, internal organ, and / or bone tissue according to PCWG3 or PCWG3-modified RECIST vl. l criteria. Optionally, the individual shows said clinical efficacy following treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3. Optionally, the method of treatment further comprises administering to the individual an androgen receptor axis-targeting agent, such as abiraterone or enzalutamide.

[0110] The term "treat", "treating", "treatment" as used herein refers to any type of intervention or process performed on an individual or the administration of an active agent or combination of active agents to an individual with the objective of curing or improving the disease or the symptoms of the disease. This includes reversing, alleviating, ameliorating, inhibiting, or slowing down the symptoms, complications, conditions, or biochemical indicia associated with the disease, as well as preventing the onset, worsening, development, severity, or recurrence of the symptoms, complications, conditions, or biochemical indicia associated with the disease.

[0111] Any method disclosed herein in relation to any use of the method of treatment of the application is equally applicable in the method of treatment of the application and vice versa.

[0112] Any method disclosed herein in relation to any use of the method of treatment of the application is equally applicable in any use in the manufacture of a medicament for the treatment of the application and vice versa.

[0113] Any method disclosed herein in relation to any use of the method of treatment of the application is equally applicable in any use in the manufacture of a medicament for the treatment of the application and vice versa.

[0114] As used herein, "effective treatment" or "positive therapeutic response" refers to treatment that produces a beneficial effect, such as amelioration of at least one symptom of a disease or condition, e.g., cancer. The beneficial effect can take the form of an improvement over baseline, including an improvement over a measurement or observation made prior to the initiation of treatment according to the method. For example, the beneficial effect can take the form of slowing down, stabilizing, halting, or reversing the progression of cancer in an individual at any clinical stage, as evidenced by a reduction or elimination of clinical or diagnostic symptoms of the disease or markers of cancer. Effective treatment may, for example, shrink tumor size, reduce the presence of circulating tumor cells, reduce or prevent metastasis of a tumor, slow down or stop tumor growth, and / or prevent or delay tumor recurrence or relapse.

[0115] The terms "therapeutic amount" or "effective amount" are used interchangeably herein and refer to the amount of an agent or combination of agents that provides the desired biological, therapeutic, and / or prophylactic result. That result can be the reduction, improvement, palliation, remission, delay, and / or slowing down of one or more signs, symptoms, or causes of a disease, or any other desired alteration in a biological system. Alternatively, a therapeutic amount is an amount sufficient to delay tumor progression. Alternatively, a therapeutic amount is an amount sufficient to prevent or delay tumor recurrence.

[0116] A therapeutic amount of the drug or composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow down, and possibly stop cancer cell infiltration into peripheral organs; (iv) inhibit tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of a tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer.

[0117] The therapeutic amount can vary depending on factors such as the disease state, age, sex, and weight of the individual to be treated, and the ability of the agent or combination of agents to elicit a desired response in the individual.

[0118] The therapeutic amount can be administered in one or more administrations.

[0119] The therapeutic amount also includes an amount that balances any toxic or deleterious effects of the agent or combination of agents with the therapeutic benefits.

[0120] Notably, loss of tumor suppressor genes is particularly common in CRPC and is associated with aggressive disease and poor prognosis. In order to effectively inhibit tumor growth with the bispecific antibodies disclosed herein, such as zanu-tamab, or the ERBB3-specific antibodies disclosed herein, intact signaling pathways downstream of the PI3K pathway can be necessary. Thus, optionally, the castration-resistant prostate cancer to be treated does not have a PTEN loss, or does not have a PTEN deficiency. Optionally, the cancer treated according to the present application is characterized by having a wild-type PTEN status. Optionally, the cancer does not have a PTEN loss. Optionally, the cancer is PTEN wild-type. Optionally, the cancer does not exhibit a PTEN loss. Without being bound by theory, optionally, it is useful to classify individuals based on PTEN status prior to the start of the treatment disclosed herein, as cancers with the appropriate PTEN status can benefit more from the treatment. Individuals whose PTEN status has been determined to be wild-type PTEN or who do not have a PTEN loss can be treated with the treatment disclosed herein, or classified as eligible for the treatment.

[0121] Alternatively, optionally, the castration-resistant prostate cancer treated according to the present application exhibits a PTEN loss or PTEN deficiency. Optionally, the cancer treated according to the present application is characterized by having a PTEN loss status. Optionally, the cancer has a PTEN loss. Optionally, the cancer is not PTEN wild-type. Optionally, the cancer exhibits a PTEN loss. Without being bound by theory, optionally, it is useful to classify individuals based on PTEN status prior to the start of the treatment disclosed herein, as cancers with the appropriate PTEN status can benefit more from the treatment. Individuals whose PTEN status has been determined to be non-PTEN wild-type or who have a PTEN loss can be treated with the treatment disclosed herein, or classified as eligible for the treatment.

[0122] The PTEN status can be determined by methods known to those of ordinary skill in the art, and any suitable method can be used in combination with the methods of treatment, or in combination with the antibodies of the present application, including combination therapies as described herein. Optionally, the PTEN status is determined using IHC. Optionally, the PTEN status is determined using a liquid biopsy method.

[0123] For example, a commercially available PTEN gene test can be used to determine the PTEN status of a body fluid or blood sample cell. A variety of methods can be used, and many are known in the art. One method is to use primers spanning the PTEN cDNA or genomic DNA for PCR amplification, followed by sequencing of the amplified nucleotide molecules. This can be done for known mutations that occur and affect PTEN activity. New mutations can also be readily detected by techniques known to one of ordinary skill in the art, including by next generation DNA or RNA sequencing. Other methods to determine PTEN status are by ELISA.

[0124] Nucleic acid based technologies can be used to determine PTEN status, including allele specific RNA based methodologies including RT-PCR, real time PCR, transcriptome analysis, anchored multiplex PCR, nCounter, FISH, DNA based methodologies including next generation sequencing technologies (NGS) based on hybrid capture, NGS based on amplicons, and other commercially available technologies. In addition, PTEN deletions can be determined using protein based assays such as immunostaining, IHC, FISH or similar technologies. To date, robust clinical testing methods have been developed using immunohistochemistry and fluorescence in situ hybridization, using diagnostic tissue specimens and circulating tumor cells in plasma, PTEN protein and gene deletions can be reproducibly measured. In particular, the IHC workflow has been successfully validated on the Ventana Benchmark platform in a Clinical Laboratory Improvement Amendments certified laboratory with high inter-observer reproducibility of the scoring system.

[0125] One example of a commercial kit to establish PTEN status is the use of the which is an analytically validated comprehensive tissue genomic profiling panel that includes TMB, MSI status, and PD-L1 IHC. The Guardant360 TissueNext report contains 84 genes. This kit can perform single nucleotide (SNV) and indel variant genotyping on 84 genes, including PTEN, amplification of 20 genes, and fusion identification of 12 genes. Another example of a commercial kit that can be used to establish PTEN status is the Roche Ventana Optiview kit DAB, which uses the SP218 PTEN antibody.

[0126] Accordingly, the present application also provides a method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the individual for said treatment if the sample does not exhibit a PTEN deletion.

[0127] Alternatively, the present application provides a method of determining whether an individual having castration-resistant prostate cancer is likely to respond to treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting a sample that does not exhibit a PTEN deletion, thereby establishing that the individual from which the sample was derived is likely to respond to said treatment.

[0128] Alternatively, the present application provides a method of classifying an individual having castration-resistant prostate cancer based on the PTEN status prior to treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) classifying the individual from which the sample was derived as eligible for said treatment if the sample does not exhibit a PTEN deletion.

[0129] The present application also provides a method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the individual for said treatment if the sample exhibits a PTEN deletion.

[0130] Alternatively, the present application provides a method of establishing whether an individual having castration-resistant prostate cancer is likely to respond to treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting a sample that exhibits a PTEN deletion, thereby establishing that the individual from which the sample was derived is likely to respond to said treatment.

[0131] Alternatively, the present application provides a method of classifying an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3 based on the PTEN status prior to the treatment, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) classifying the sample-derived individual as eligible for the treatment if the sample exhibits a PTEN loss.

[0132] Alternatively, the PTEN loss or PTEN status is determined using IHC. In another aspect, the PTEN status is determined using a liquid biopsy assay comprising DNA sequencing.

[0133] Alternatively, the cancer or individual to be treated by the present application does not have a oncogenic driver mutation. Alternatively, the cancer or individual does not have a oncogenic driver mutation in the PI3K, AKT, mTOR pathway. Alternatively, the cancer or individual does not have an upregulation of the pathway. Alternatively, the cancer or individual does not have a mutation in any of EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET and ROS1. Alternatively, the cancer or individual does not have a mutation in a known tumor-associated gene or protein encoded thereby, such as EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET and ROS1.

[0134] Alternatively, the cancer of the individual is tested by next generation sequencing (e.g. DNA, RNA or whole transcriptome) and thereafter the cancer or individual is screened for treatment with a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3 using a method comprising the steps of: a) determining the presence of an oncogenic driver mutation, optionally a mutation that modulates the PI3K, AKT and / or mTOR pathway, in a sample obtained from the individual; b) classifying the sample-derived individual as eligible for the treatment if the sample lacks the presence of an oncogenic driver mutation, optionally a mutation that modulates the PI3K, AKT and / or mTOR.

[0135] Optionally, the cancer of the individual is tested by next generation sequencing (e.g., DNA, RNA, or whole transcriptome), and then the cancer or individual is screened for treatment with a bispecific antibody comprising an antigen binding site that can bind an extracellular portion of ERBB2 and an antigen binding site that can bind an extracellular portion of ERBB3 using a method comprising the steps of: a) determining the presence of a oncogenic driver mutation in a sample obtained from the individual, optionally a mutation in EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1; b) classifying the sample-derived individual as eligible for the treatment if the sample lacks the presence of a oncogenic driver mutation, optionally a mutation in EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1.

[0136] Optionally, a CRPC or individual with CRPC is screened for treatment with a bispecific antibody comprising an antigen binding site that can bind an extracellular portion of ERBB2 and an antigen binding site that can bind an extracellular portion of ERBB3 using a method comprising the steps of: a) determining the presence of a oncogenic driver mutation in a sample obtained from the individual's CRPC, optionally the mutation modulates the PI3K, AKT, and / or mTOR pathway; b) classifying the sample-derived individual as eligible for the treatment if the sample lacks the presence of a oncogenic driver mutation, optionally a mutation that modulates PI3K, AKT, and / or mTOR.

[0137] Optionally, a CRPC or individual with CRPC is screened for treatment with a bispecific antibody comprising an antigen binding site that can bind an extracellular portion of ERBB2 and an antigen binding site that can bind an extracellular portion of ERBB3 using a method comprising the steps of: a) determining the presence of a oncogenic driver mutation in a sample obtained from the individual, optionally a mutation in EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1; b) classifying the sample-derived individual as eligible for the treatment if the sample lacks the presence of a oncogenic driver mutation, optionally a mutation in EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1.

[0138] Optionally, the sample obtained from the individual is a sample taken from a tumor or cancer prior to the anti-CRPC treatment of the application. Optionally, the sample obtained from the individual is a sample comprising tumor or cancer cells from a tumor or cancer that the individual is to be treated for. Optionally, the sample taken from a tumor or cancer is obtained prior to the initiation of the anti-CRPC treatment of the application.

[0139] As used herein, the term "antigen binding site" refers to a site derived from, and preferably present on, a bispecific antibody that is capable of binding an antigen. An antigen binding site is typically formed by and present in a variable domain of an antibody. The variable domain comprises the antigen binding site. An antigen binding site can bind to an antigen under normal physiological conditions. This is also commonly referred to as the antigen binding site "binding" to the antigen.

[0140] In one embodiment, the antibody variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL). The antigen binding site can be present in the combined VH / VL variable domain, or only in the VH region or only in the VL region. When the antigen binding site is only present in one of the two regions of the variable domain, the other variable region can contribute to the folding and / or stability of the binding variable region, but does not significantly contribute to the binding to the antigen.

[0141] As used herein, antigen binding refers to the typical binding ability of an antibody to its antigen. An antibody comprising an antigen binding site that binds to ERBB2 binds to the homologous receptors ERBB1 and ERBB4 of the same species at least 100-fold less under otherwise identical conditions. An antibody comprising an antigen binding site that binds to ERBB3 binds to ERBB3 and does not bind to the homologous receptors ERBB1 and ERBB4 of the same species under otherwise identical conditions.

[0142] Given that the ERBB family is a family of cell surface receptors, binding is typically assessed on cells expressing the receptor. Binding of an antibody to an antigen can be assessed in a variety of ways. One way is to let the antibody stand with the antigen, preferably a cell expressing the antigen, remove the unbound antibody, preferably by a washing step, and detect the bound antibody by a labeled antibody that binds to the bound antibody.

[0143] Binding of an antibody to an antigen is typically mediated by the complementary regions of the antibody, and the specific three-dimensional structure of the antigen and the variable domain, which allows these two structures to bind together precisely (similar to the interaction of a lock and key), as opposed to random, non-specific sticking of the antibody. Since the antibody typically recognizes an epitope of the antigen, and this epitope can also be present in other compounds, the antibodies of the present application that bind to ERBB2 and / or ERBB3 can also recognize other proteins if the other compound contains the same epitope. Thus, the term "binds" does not exclude binding of the antibody to another protein or a protein containing the same epitope. Such other proteins are preferably non-human proteins. The ERBB2 antigen binding sites and the ERBB3 antigen binding sites defined herein typically do not bind to other proteins on the cell membrane of a postnatal, preferably adult, human cell.

[0144] As used herein, the term "interferes with binding" means that the antibody is directed against an epitope on ERBB3 and the antibody competes with a ligand for binding to ERBB3. The antibody can reduce ligand binding, displace the ligand, or it can at least partially prevent a ligand from binding to ERBB3, e.g., by steric hindrance, when the ligand is already bound to ERBB3.

[0145] The term "antibody" as used herein means a proteinaceous molecule, preferably belonging to the immunoglobulin class of proteins, which contains one or more variable domains that can bind to an epitope on an antigen, wherein such domains are derived from or share sequence homology with the variable domains of antibodies. Antibodies for therapeutic use are preferably as close to natural antibodies of the individual to be treated as possible (e.g., human antibodies for human individuals). Antibody binding can be expressed in terms of specificity and affinity. Specificity determines which antigen or epitope thereof the binding domain specifically binds to. Affinity is a measure of the strength of binding to a particular antigen or epitope. Antibodies, such as the bispecific antibodies of the present invention, comprise the constant domains (Fc portion) of natural antibodies. Antibodies of the present invention are typically bispecific full-length antibodies, preferably of the human IgG subgroups. Preferably, the antibodies disclosed herein are of the human IgGl subgroup. Such antibodies have good ADCC properties, have a favorable half-life after administration into the human body, and there are currently CH3 engineering technologies available that can provide modified heavy chains that, when co-expressed in a clonal cell, preferentially form heterodimers rather than homodimers.

[0146] The antibodies disclosed herein are preferably "full-length" antibodies. The term "full-length" is defined to comprise essentially intact antibodies, but which do not necessarily have all the functions of intact antibodies. For the avoidance of doubt, a full-length antibody comprises two heavy chains and two light chains. Each chain comprises a constant region (C) and a variable region (V), which can be further divided into CHI, CH2, CH3, VH, and CL, VL domains (suitable amino acid sequences for each domain are set forth in Table 1 below). Figure 1 a to If and Figure 2A full length antibody is a monoclonal antibody that has a structure generally found in native antibodies. This includes an Fc region and two antigen binding regions or arms. The antigen binding regions are each comprised of a variable region linked to a constant region. The variable region is comprised of three variable domains (VH / VL pairs) that are each comprised of a heavy chain variable domain (VH) and a light chain variable domain (VL). The constant region is comprised of three constant domains (CH1 / CL pairs) that are each comprised of a heavy chain constant domain (CH1) and a light chain constant domain (CL). The variable domains are responsible for binding to the antigen, while the constant domains are responsible for mediating interactions with the immune system. The term "full length antibody" encompasses antibodies in which mutations can be present that provide the desired characteristics. Such mutations should not be a large portion of any region. However, antibodies in which one or several amino acid residues are deleted without substantially altering the binding characteristics of the resulting antibody are included within the term "full length antibody." For example, an IgG antibody can have 1-20 amino acid residue insertions, deletions, or combinations thereof in the constant region. For example, when the antibody itself has low ADCC activity, the ADCC activity of the antibody can be increased by slightly modifying the constant region of the antibody (Junttila, T. T., K. Parsons, et al. (2010). "Superior In vivo Efficacy of Afucosylated Trastuzumab in the Treatment of HER2-Amplified Breast Cancer." Cancer Research 70(11): 4481-4489).

[0147] Full length IgG antibodies are preferred because they have a better half-life, and for immunogenic reasons it is desirable to have a molecule that is as close to completely autologous (human) as possible. The antibodies disclosed herein are preferably bispecific IgG antibodies, preferably bispecific full length IgG1 antibodies. IgG1 is preferred because of its long circulating half-life in humans. To prevent any immunogenicity in humans, the bispecific IgG antibody is preferably human IgG1.

[0148] The term "bispecific" (bs) refers to an antibody having one portion (as defined above) that binds to one epitope on an antigen and another portion that binds to a different epitope. The different epitopes are usually present on different antigens. The heavy chain variable regions of a bispecific antibody are usually different from each other, while the light chain variable regions are preferably the same. Bispecific antibodies in which the different heavy chain variable regions are combined with the same or a common light chain are also referred to as bispecific antibodies with a common light chain. The bispecific antibodies described herein usually comprise one variable domain that binds to ERBB2 and another variable domain that binds to ERBB3.

[0149] Preferred bispecific antibodies can be obtained by co-expressing two different heavy chains and one common light chain in a single cell. When using wild-type CH3 domains, co-expression of two different heavy chains and one common light chain will result in three different species: AA, AB and BB. To increase the percentage of the desired bispecific product (AB), CH3 engineering can be employed, or in other words, heavy chains with compatible heterodimerization domains can be used, as defined below. Suitable compatible CH3 heterodimerization domains are, for example Figure 2 d and Figure 2 e.

[0150] The term "compatible heterodimerization domain" as used herein refers to a protein domain that is engineered such that the engineered domain A' will preferentially form a heterodimer with the engineered domain B', and vice versa, while homodimerization between A'-A' and B'-B' is reduced.

[0151] The term "common light chain" refers to a light chain that can be identical or have some amino acid sequence differences that do not affect the binding specificity of the full-length antibody. For example, light chains that are not identical but functionally equivalent can be made or discovered, for example by introducing and testing conservative amino acid changes, amino acid changes in regions that do not or only partially contribute to the binding specificity when paired with a heavy chain, and similar changes. The terms "common light chain", "common VL", "single light chain", "single VL", with or without the term "rearranged" are used interchangeably herein.

[0152] The common light chain (variable region) preferably has a germline sequence. A preferred germline sequence is a light chain variable region that is frequently used in the human repertoire and has good thermodynamic stability, yield, and solubility. In a preferred embodiment, the light chain comprises a light chain region comprising the amino acid sequence of the IgV kappa 1-39*01 gene segment as shown in Figure 1 a to If, more preferably a common light chain IGKV1-39 / jk1 having 0-10, preferably 0-5 amino acid insertions, deletions, substitutions, additions, or combinations thereof. IgV kappa 1-39 is an abbreviation for the immunoglobulin variable kappa 1-39 gene. The gene is also known as immunoglobulin kappa variable 1-39; IGKV139; or IGKV1-39. The gene has the external ID HGNC:5740; Entrez Gene: 28930; Ensembl: ENSG00000242371. The variable region of IGKV1-39 is listed in Figure 1 a to If. The V region can be combined with one of five J regions. Figure 1a-f describe two preferred sequences of IgVκ1-39 in combination with J region. The joined sequence is denoted IGKV1-39 / jk1 and IGKV1-39 / jk5; another designation is IgVκ1-39*01 / IGJκ1*01 or IgVκ1-39*01 / IGJκ5*01 (nomenclature according to IMGT database on international web page imgt.org).

[0153] Preferably, the IgVκ1-39*01 comprising light chain variable region is a germline sequence. More preferably, the IGJκ1*01 or / IGJκ5*01 comprising light chain variable region is a germline sequence. In a preferred embodiment, the IGKV1-39 / jk1 or IGKV1-39 / jk5 light chain variable region is a germline sequence.

[0154] In a preferred embodiment, the light chain variable region comprises the germline IgVκ1-39*01. In a preferred embodiment, the light chain variable region comprises the κ light chain IgVκ1-39*01 / IGJκ1*01 or IgVκ1-39*01 / IGJκ5*01. In a preferred embodiment, the IgVκ1-39*01 / IGJκ1*01. The light chain variable region preferably comprises the germline κ light chain IgVκ1-39*01 / IGJκ1*01 or the germline κ light chain IgVκ1-39*01 / IGJκ5*01, preferably the germline IgVκ1-39*01 / IGJκ1*01.

[0155] The skilled person will recognize that "common" also refers to functional equivalents of light chains whose amino acid sequence is not identical. There are many variants of said light chains in which there are mutations (deletions, substitutions, additions) that do not substantially affect the formation of the functional binding region. The light chain can also be a light chain with 1-5 amino acid insertions, deletions, substitutions or combinations thereof as described above.

[0156] Preferably, the first antigen binding site and the second antigen binding site each comprise a light chain variable region comprising a CDR1 having the sequence (RASQSISSYLN), a CDR2 having the sequence (AASSLQS), and a CDR3 having the sequence (QQSYSTPPT), the CDRs being QSISSY, AAS and QQSYSTPPT, respectively, according to the KABAT numbering or according to the IMGT numbering system.

[0157] The antibodies disclosed herein can reduce ligand-induced receptor function of ERBB3 on ERBB2 and ERBB3 positive cells. In the presence of excess ERBB2, ERBB2 / ERBB3 heterodimers can provide a growth signal to the expressing cell in the absence of detectable ligand to the ERBB3 chain in the heterodimer. This ERBB3 receptor function is referred to herein as ligand-independent receptor function of ERBB3.

[0158] ERBB2 / ERBB3 heterodimers also provide growth signals to cells expressing both receptors in the presence of an ERBB3 ligand. This ERBB3 receptor function is referred to herein as ligand-induced ERBB3 receptor function.

[0159] The term "ERBB3 ligand" as used herein refers to a polypeptide that binds to and activates ERBB3. Examples of ERBB3 ligands include, but are not limited to, neuregulin 1 (NRG) and neuregulin 2, betacellulin, heparin-binding epidermal growth factor, and epiregulin. The term includes biologically active fragments of naturally occurring polypeptides and / or variants thereof.

[0160] Preferably, the ligand-induced receptor function of ERBB3 is the growth of ERBB2 and ERBB3 positive cells induced by an ERBB3 ligand. In a preferred embodiment, the cells are MCF-7 cells HTB-22 TM ); SKBR3( HTB-30 TM ) cells; NCI-87( CRL-5822 TM ) cells; BxPC-3-luc2 cells (Perkin Elmer 125058), BT-474 cells( HTB-20 TM ) JIMT 1 cells (DSMZ no.: ACC 589).

[0161] The ERBB2 protein comprises several domains (see Landgraf, R Breast Cancer Res. 2007; 9(1): 202- for a review of the structure and function of the ERBB2 protein Figure 1a to If). The extracellular domains are referred to as domains I-IV. The positions to which the various domains of the antigen binding site of the antibodies described herein bind have been mapped. Bispecific antibodies having an antigen binding site of domain I or domain IV that binds ERBB2 (first antigen binding site) comprise a heavy chain variable region that, when combined with each light chain, maintains significant binding specificity and affinity for ERBB2. Bispecific antibodies having an antigen binding site of domain I or domain IV that binds ERBB2 (first antigen binding site) and an antigen binding site that binds ERBB3 (second antigen binding site) can more effectively reduce ligand-induced receptor function of ERBB3 when compared to bispecific antibodies comprising an antigen binding site that binds to another extracellular domain of ERBB2 (first antigen binding site). Bispecific antibodies comprising an antigen binding site of domain I or domain IV that binds ERBB2 (first antigen binding site) are preferred. Preferably, the antigen binding site binds to domain IV of ERBB2. Preferred antibodies comprise a first antigen binding site that binds to domain I of ERBB2 and a second antigen binding site that binds to domain III of ERBB3.

[0162] In a preferred embodiment, the antibody comprises an antigen binding site that binds at least one amino acid of domain I of ERBB2 selected from the group consisting of T144, T164, R166, P172, G179, S180, and R181, and surface-exposed amino acid residues located within about 5 amino acid positions from T144, T164, R166, P172, G179, S180, or R181.

[0163] In a preferred embodiment, the antibody preferably comprises an antigen binding site that binds at least one amino acid of domain III of ERBB3 selected from the group consisting of R426 and surface-exposed amino acid residues located within about 5 amino acid positions from R426 in the native ERBB3 protein. In a preferred embodiment, the antibody preferably comprises an antigen binding site that binds at least one amino acid of domain III of ERBB3 selected from the group consisting of R426 and surface-exposed amino acid residues located within about 5 amino acid positions from R426 in the native ERBB3 protein.

[0164] Bispecific antibodies having an antigen binding site that binds ERBB2 (first antigen binding site) and further comprising ADCC are more effective than other ERBB2 binding antibodies that do not have significant ADCC activity, particularly in vivo. Thus, bispecific antibodies that exhibit ADCC are preferred. Antibodies with greater ability to mediate the desired cytotoxic activity of anticancer Mabs can be generated by engineering the Fc region (by introducing amino acid substitutions) to bind with higher selectivity to the activating receptors.

[0165] One technique to enhance ADCC of an antibody is afucosylation. (See, e.g., Junttila, T. T., K. Parsons, et al. (2010). "Superior In vivo Efficacy of Afucosylated Trastuzumab in the Treatment of HER2-Amplified Breast Cancer." Cancer Research 70(11): 4481-4489). Thus, further provided are the bispecific antibodies disclosed herein that are afucosylated. Alternatively or additionally, various other strategies can be used to achieve ADCC enhancement, including, for example, glycoengineering and mutation induction, all of which seek to enhance Fc binding to low-affinity activating FcyRIIIa and / or reduce binding to low-affinity inhibiting FcyRIIb.

[0166] There are several in vitro methods to determine the efficacy of an antibody or effector cell to elicit ADCC. These include the chromium 51 [Cr51] release assay, the europium [Eu] release assay, and the sulfur 35 [S35] release assay. Typically, a labeled target cell line expressing a particular surface-exposed antigen is incubated with an antibody specific for that antigen. After washing, effector cells expressing the Fc receptor CD 16 are typically incubated with the antibody-labeled target cells. Lysis of the target cells is then typically measured by release of an intracellular label, such as by scintillation counter or spectrophotometric methods.

[0167] Alternatively, the antibodies disclosed herein are for use in humans. Thus, alternatively, the antibodies are human or humanized antibodies. Human tolerance to a polypeptide is controlled by a number of different factors. Immunogenicity, whether T cell mediated, B cell mediated, or otherwise, is one of the variables included in human tolerance to a polypeptide. The constant region of the bispecific antibody is preferably a human constant region. The constant region can contain one or more, preferably no more than 10, more preferably no more than 5, amino acid differences from a naturally occurring human antibody constant region. Preferably the constant portion is derived entirely from a naturally occurring human antibody. The various antibodies produced herein are derived from a human antibody variable domain library. Thus, the variable domains are human. The unique CDR regions can be derived from a human, synthetic, or from another organism. When the variable region has an amino acid sequence identical to that of a variable region (except for the CDR regions) of a naturally occurring human antibody, the variable region is considered to be a human variable region. In the antibodies, the variable region of the VH that binds to ERBB2, the variable region of the VH that binds to ERBB3, or the light chain, can contain one or more, preferably no more than 10, more preferably no more than 5, amino acid differences from one or more of the naturally occurring human antibody variable regions, with the possible exception of differences in the amino acid sequence of the CDR regions. Such mutations also occur in nature in the case of somatic hypermutation.

[0168] The antibodies can be derived from a variety of animal species, at least with respect to the heavy chain variable region. It is common practice to humanize such, for example, murine heavy chain variable regions. This can be accomplished in a number of ways, one of which is to graft the CDRs into a human heavy chain variable region that has a 3D structure that matches that of the murine heavy chain variable region; deimmunization of the murine heavy chain variable region, preferably by removing known or suspected T cell or B cell epitopes from the murine heavy chain variable region. The removal is typically accomplished by substituting one or more of the amino acids in the epitope for another, typically conserved, amino acid, such that the sequence of the epitope is modified so that it is no longer a T cell epitope or a B cell epitope.

[0169] Such deimmunized murine heavy chain variable regions are less immunogenic in humans than the original murine heavy chain variable regions. Preferably, the variable regions or domains are further humanized, such as, for example, veneered. By using veneering techniques, external residues that are prone to encounter the immune system are selectively replaced with human residues to provide a hybrid molecule comprising a veneered surface that is weakly immunogenic or substantially non-immunogenic. The animals used in the present invention are preferably mammals, more preferably primates, and most preferably humans.

[0170] Optionally, the antibodies disclosed herein comprise a constant region of a human antibody. Antibodies are classified into five classes or isotypes: IgG, IgA, IgM, IgD and IgE, based on the differences in the heavy chain constant domains. These classes or isotypes comprise at least one of the heavy chains designated by the corresponding Greek letter. Optionally, the constant region comprises an IgG constant region, optionally, an IgGl constant region, optionally, a mutated IgGl constant region. Some variations in the IgGl constant region occur in nature, such as (for example) allotypes G1m1, 17 and G1m3, and / or are permissible without altering the immunological properties of the resulting antibody. Generally, about 1-10 amino acid insertions, deletions, substitutions or combinations thereof are permissible in the constant region.

[0171] Optionally, the antibodies of the present application, including but not limited to bispecific antibodies, comprise an antigen binding site that can bind to an extracellular portion of ERBB3 that blocks ERBB3 and its ligand heregulin. Optionally, the antibody also comprises an antigen binding site that can bind to domain III of an extracellular portion of ERBB3. Optionally, the antibody also comprises an antigen binding site that can bind to an extracellular portion of ERBB2. Optionally, the antibody comprises an antigen binding site that can bind to an extracellular portion of ERBB2 and an antigen binding site that can bind to an extracellular portion of ERBB3. Bispecific antibodies of the present application comprise a first antigen binding site that binds to an extracellular portion of ERBB2 and a second antigen binding site that binds to an extracellular portion of ERBB3. Optionally, the bispecific antibody has a first antigen binding site that binds to domain I of ERBB2 and a second antigen binding site that binds to domain III of ERBB3. Optionally, the affinity of the first antigen binding site for ERBB2 is lower than the affinity of the second antigen binding site for ERBB3. Optionally, the bispecific antibody is or comprises Zenocutuzumab (International Nonproprietary Name).

[0172] Optionally, the cancer is non-NRG1 fusion positive. Non-NRG1 fusion positive or non-NRG1 fusion negative means that any cancer or individual referred to herein does not comprise an NRG1 fusion gene, in particular the individual or cancer does not comprise an NRG fusion gene that expresses a protein comprising an NRG1 EGF-like domain. Optionally, the individual comprises a cancer-associated cell, such as a cancer-associated fibroblast, that is non-NRG1 fusion positive. The cancer-associated cell is typically located in a human prostate.

[0173] The bispecific antibody of the present invention comprises a first antigen-binding site that binds to the extracellular portion of ERBB2 and a second antigen-binding site that binds to the extracellular portion of ERBB3. Optionally, the bispecific antibody has a first antigen-binding site that binds to domain I of ERBB2 and a second antigen-binding site that binds to domain III of ERBB3. Optionally, the first antigen-binding site has a lower affinity for ERBB2 than the second antigen-binding site has for ERBB3.

[0174] Optionally, the bispecific antibody contains

[0175] i) at least CDR1, CDR2, and CDR3 sequences in an ERBB2-specific heavy chain variable region selected from the group consisting of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, and MF3003, or wherein the antibody comprises a CDR sequence that differs from the following CDR1, CDR2, and CDR3 sequences by up to 3 amino acids, preferably up to 2 amino acids, and preferably up to 1 amino acid: MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, or MF3003; and / or

[0176] ii) At least CDR1, CDR2 and CDR3 sequences in the ERBB3-specific heavy chain variable region, which is selected from the group consisting of: MF3178; MF3176;

[0177] MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or wherein the antibody comprises up to 3 amino acids of the following CDR1, CDR2, and CDR3 sequences, preferably The following CDR sequences have at most two amino acids, preferably at most one amino acid: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074.

[0178] Optionally, the bispecific antibody comprises

[0179] i) an ERBB2-specific heavy chain variable region sequence selected from the group consisting of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 and MF3003, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 or MF3003 by up to 15 amino acids; and / or

[0180] ii) an ERBB3-specific heavy chain variable region sequence selected from the group consisting of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074 by up to 15 amino acids.

[0181] Optionally, the bispecific antibody for use in the application is MF3958 x MF3178 comprising heavy chain variable region MF3958 (anti-ERBB2) and MF3178 (anti-ERBB3). MF3958 x MF3178 has been shown to be well tolerated as a single agent with low immunogenicity risk in over 100 patients treated, making it an excellent drug for combination therapy, with advantages over other anti-ERBB2 and / or anti-ERBB3 targeting agents. Without being bound by any theory, the efficacy of MF3958 x MF3178 in treating patients with cancer harboring ERBB2 and ERBB3 positive cells with ERBB3 mutations is believed to be based on the epitope specificity and affinity imbalance of MF3958 x MF3178, allowing MF3958 x MF3178 to dock to domain 1 of ERBB2 and prevent ERBB3 from dimerizing with ERBB2 at domain 3, thereby disrupting activation of the PI3K pathway.

[0182] The bispecific antibody comprises the variable domain of the first antigen binding site and the variable domain of the second antigen binding site, preferably comprising a light chain variable region comprising a CDR1 having the sequence (RASQSISSYLN), a CDR2 having the sequence (AASSLQS), and a CDR3 having the sequence (QQSYSTPPT), each CDR being QSISSY, AAS, and QQSYSTPPT, respectively, according to the IMGT numbering system.

[0183] The bispecific antibody comprises the variable domain of the first antigen binding site and the variable domain of the second antigen binding site, preferably comprising a light chain variable region and / or CDR1, CDR2, and CDR3 having the sequences of QSISSY, AAS, and QQSYSTPPT, respectively, according to the IMGT numbering system. Figure 1 a or Figure 1 b, and / or CDR1, CDR2, and CDR3 having the sequences of QSISSY, AAS, and QQSYSTPPT, respectively, according to the IMGT numbering system. Figure 1 f).

[0184] The amount of bispecific antibody to be administered to an individual is typically within a therapeutic window, meaning that an amount sufficient to achieve a therapeutic effect is used, while the amount does not exceed a threshold that results in an unacceptable degree of side effects. The dosage level selected will depend on a variety of factors, including the route of administration, the time of administration, the rate of excretion of the specific compound being employed, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the individual undergoing therapy, and like factors well known in the medical arts. The dosage range is 200-1000 mg, once a week, every two weeks, or every three weeks. Preferably, the administration of the therapeutic agent of the application targeting ERBB2 x ERBB3 follows a dosing regimen of 750 mg every week, every two weeks, or every three weeks, preferably a dose of 750 mg every two weeks or every three weeks. Preferably, administration is to an individual having a cancer with a solid tumor harboring an ERBB3 mutation, after which the dosing regimen comprises a fixed dose administration of 400 mg every week, preferably starting after a single administration of 800 mg. After this alternative dosing regimen, the bispecific antibody of the application is preferably administered at a dose of 400 mg every week for 3 weeks, followed by 1 week without administration. This is followed by one or more four-week cycles consisting of a fixed dose of 400 mg three times a week, followed by one week without administration. This regimen is preferably continued until a therapeutic effect is observed. The dosing regimen of the application comprises a biweekly cycle, wherein after an initial administration of 750 mg as a four-hour infusion, a fixed dose of 750 mg every week is started, followed by 750 mg as a two-hour infusion every two weeks, for a cycle of 4 weeks. This regimen is preferably continued until a therapeutic effect is observed.

[0185] Administration preferably involves intravenous injection of two infusions of the bispecific antibody of the application to reach the full dose, preferably > 360 mg of antibody. Alternatively, the full dose can be administered in a single infusion at a lower dose, for example when the antibody dose is < 360 mg. Pre-medication can be included in the administration regimen to mitigate infusion-related reactions.

[0186] Preferably, the treatment comprises stabilizing the tumor in size or lesion, or preventing further growth of the tumor, including shrinking the tumor. Preferably, the treatment or administration is with the bispecific antibody of the application in a weekly regimen, and for a period of at least 1, 2, 4, 8, or at least 12 months. Preferably, the subsequent dosing regimen comprises a weekly cycle of a fixed dose of 400 mg every week, starting after an initial administration of 800 mg. From week 3, the bispecific antibody of the application is administered at a dose of 400 mg every week for 3 weeks, followed by 1 week without administration of the bispecific antibody of the application. Alternatively, the subsequent dosing regimen comprises a biweekly cycle, wherein after an initial administration of 750 mg as a four-hour infusion, a fixed dose of 750 mg every week is started, followed by 750 mg as a two-hour infusion every two weeks, for a cycle of 4 weeks. Another alternative comprises administering a fixed dose of 750 mg every three weeks to each individual.

[0187] Preferably, the bispecific antibody has a first antigen binding site that binds or can bind an extracellular part of ERBB2 and a second antigen binding site that binds or can bind an extracellular part of ERBB3, in particular MF3958 x MF3178, stabilizes tumors of castration-resistant prostate cancer in size or lesion, or the treatment prevents further tumor growth of castration-resistant prostate cancer.

[0188] The antibodies of the present application can be formulated as pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and additional, optional active agents. The antibodies and compositions comprising the antibodies can be administered by any route, including parenteral, enteral, and topical administration. Parenteral administration is typically by injection and includes, for example, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, intratumoral, intrasternal, and intramuscular injection and infusion.

[0189] The present application provides bispecific antibodies for use in the methods and treatments described herein. Suitable bispecific antibodies comprise a first antigen binding site that binds or can bind ERBB2 and a second antigen binding site that binds or can bind ERBB3. The bispecific antibodies reduce or can reduce ligand-induced receptor function of ERBB3 on ERBB2 and ERBB3 positive cells and / or disrupt ERBB2 and ERBB3 heterodimerization. Preferred antibodies and their preparation are disclosed in WO 2015 / 130173, which is incorporated herein by reference. The examples in WO 2015 / 130173 further describe many properties of the antibodies, such as ligand binding and epitope mapping localization.

[0190] Alternatively, the present application provides antibodies that bind or can bind ERBB3. Alternatively, the antibody binds domain III of ERBB3 and comprises CDR1, CDR2, and CDR3 sequences as disclosed herein. Alternatively, the antibody is a monospecific antibody, such as patritumab (U3-1287 / A888), seribantumab (MM-121), lumretuzumab (RG7116, RO-5479599), elgemtumab (LJM716), AV-203, KTN3379 (CDX-3379), or GSK2849330. Alternatively, the antibody is an antibody-drug conjugate, such as patritumab deruxtecan (U3-1402). Alternatively, the antibody is a monospecific bivalent antibody.

[0191] Alternatively, patritumab is administered at 18 mg / kg once every 21 days, followed by 9 mg / kg once every 21 days.

[0192] Alternatively, seribantumab is administered at a loading dose of 40 mg / kg, followed by a maintenance dose of 20 mg / kg weekly (40 / 20 mg / kg). The dose or schedule can be adjusted at the discretion of the treating physician. Alternatively, seribantumab is administered at a dose of 3 g weekly, administered via intravenous injection (IV).

[0193] Alternatively, lumretuzumab is administered at 500 or 1000 mg every 3 weeks via IV infusion in combination with pertuzumab, wherein pertuzumab is administered at an initial loading dose of 840 mg every 3 weeks via IV infusion, followed by a maintenance dose of 420 mg every 3 weeks via intravenous infusion.

[0194] Alternatively, patritumab deruxtecan is administered at 5.6 mg / kg intravenously every 3 weeks (q3W).

[0195] Alternatively, KTN3379 / CDX-3379 is administered at 20 mg / kg intravenously every 3 weeks (q3W). Alternatively, CDX-3379 is administered at a dose of 12 mg / kg once every three weeks in combination with cetuximab, 400 mg / m 2 cetuximab, followed by a weekly dose of 250 mg / m 2 cetuximab.

[0196] Alternatively, AV-203 is administered at 20 mg / kg intravenously every 2 weeks (q2W).

[0197] Alternatively, GSK2849330 is administered at a dose of 30 mg / kg once weekly.

[0198] Alternatively, the bispecific antibody disclosed herein comprises:

[0199] - at least the CDR3 sequence, preferably at least the CDR1, CDR2 and CDR3 sequence, in a heavy chain variable region specific for ERBB2 selected from the group consisting of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 and MF3003, or which heavy chain variable region sequence differs from the referenced heavy chain variable region sequence by no more than 15 amino acids, preferably no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, more preferably no more than 1, 2, 3, 4 or 5 amino acids; and / or

[0200] - at least the CDR3 sequence, preferably at least the CDR1, CDR2 and CDR3 sequence, in a heavy chain variable region specific for ERBB3 selected from the group consisting of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061 ; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071 ; MF6072; MF6073 and MF6074, or which heavy chain variable region sequence differs from the referenced heavy chain variable region sequence by no more than 15 amino acids, preferably no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, more preferably no more than 1, 2, 3, 4 or 5 amino acids.

[0201] Alternatively, as disclosed herein, an antibody that binds to ERBB3 but not necessarily to ERBB2 comprises:

[0202] - at least the CDR3 sequence, preferably at least the CDR1, CDR2 and CDR3 sequence, in a heavy chain variable region specific for ERBB3 selected from the group consisting of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061 ; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071 ; MF6072; MF6073 and MF6074, or which heavy chain variable region sequence differs from the referenced heavy chain variable region sequence by no more than 15 amino acids, preferably no more than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, more preferably no more than 1, 2, 3, 4 or 5 amino acids.

[0203] CDR sequences can be altered for example for optimization purposes, preferably to increase binding efficacy or stability of the antibody. Optimization is performed by for example mutagenesis protocols, followed by preferably testing the resulting antibodies for stability and / or binding affinity, and preferably selecting CDR sequences with improved ERBB2 or ERBB3-specificity. The skilled person is able to generate antibody variants comprising at least one altered CDR sequence. For example, conservative amino acid substitutions are applied. Some examples of conservative amino acid substitutions include substitution of one hydrophobic residue, such as isoleucine, valine, leucine, or methionine for another hydrophobic residue, and substitution of one polar residue for another polar residue, such as aspartic acid for glutamic acid, or glutamine for asparagine.

[0204] Alternatively, the antibody comprises a variable domain that binds to ERBB2, wherein the VH chain of the variable domain comprises the amino acid sequence of VH chain MF2973; MF3004; MF3958 (which is humanized MF2971); MF2971; MF3025; MF2916; MF3991 (which is humanized MF3004); MF3031; or MF3003; or comprises the amino acid sequence of VH chain MF2973; MF3004; MF3958 (which is humanized MF2971); MF2971; MF3025; MF2916; MF3991 (which is humanized MF3004); MF3031; or MF3003, with up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the VH chain sequence of the above. The VH chain of the variable domain that binds to ERBB2 preferably comprises the amino acid sequence of:

[0205] MF2971, or a humanized version thereof, wherein the humanized version preferably comprises the amino acid sequence of MF3958; or

[0206] MF3004 or a humanized version thereof, wherein the humanized version preferably comprises the amino acid sequence of MF3991. In one embodiment, the VH chain of the variable domain that binds to ERBB2 comprises the amino acid sequence of VH chain MF2971 or a humanized version thereof, wherein the humanized version preferably comprises the amino acid sequence of MF3958; or MF3004 or a humanized version thereof, wherein the humanized version preferably comprises the amino acid sequence of MF3991, wherein the referenced VH sequences have up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the respective sequences. In a preferred embodiment, the VH chain of the variable domain that binds to ERBB2 comprises the amino acid sequence of MF3958; or comprises the amino acid sequence of MF3958 with up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the VH chain sequence.

[0207] The VH chain that binds to the ERBB3 variable domain preferably comprises the amino acid sequence of VH chain MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; or MF6074; or the amino acid sequence of VH chain MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; or MF6074, having up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the VH chain sequence. The VH chain that binds to the ERBB3 variable domain preferably comprises the amino acid sequence of MF3178, MF3176, MF3163, MF6058, MF6061, or MF6065; or the amino acid sequence of MF3178, MF3176, MF3163, MF6058, MF6061, or MF6065, having up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the respective VH chain sequence. In a preferred embodiment, the VH chain that binds to the ERBB3 variable domain comprises the amino acid sequence of MF3178; or the amino acid sequence of MF3178, having up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or a combination thereof, relative to the VH chain sequence. Preferably, the above amino acid insertions, deletions, and substitutions are not present in the CDR3 region. Preferably, the above amino acid insertions, deletions, and substitutions are also not present in the CDR1 and CDR2 regions. Preferably, the above amino acid insertions, deletions, and substitutions are also not present in the FR4 region.

[0208] Optionally, the antibody comprises at least the CDRl, CDR2 and CDR3 sequences of MF2971, MF3958, MF3004 or MF3991, most preferably at least the CDRl, CDR2 and CDR3 sequences of MF3958. Preferably, the antibody comprises at least the CDRl, CDR2 and CDR3 sequences of MF3178, MF3176, MF3163, MF6058, MF6061 or MF6065, most preferably at least the CDRl, CDR2 and CDR3 sequences of MF3178.

[0209] Optionally, the ERBB2-specific heavy chain variable region comprises the amino acid sequence of the VH chain MF3958 with up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably up to 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or combinations thereof relative to the VH chain sequence (preferably wherein the insertions, deletions, substitutions are not in the CDRl, CDR2 or CDR3). Optionally, they are also not in the FR4 region. Optionally, the amino acid substitutions are conservative amino acid substitutions.

[0210] Optionally, the ERBB3-specific heavy chain variable region comprises the amino acid sequence of the VH chain MF3178 with up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably up to 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or combinations thereof relative to the VH chain sequence. The one or more amino acid insertions, deletions, substitutions or combinations thereof are preferably not in the CDRl, CDR2 or CDR3 regions of the VH chain. They are preferably also not in the FR4 region. The amino acid substitutions are preferably conservative amino acid substitutions.

[0211] Optionally, the ERBB2-specific heavy chain variable region comprises the amino acid sequence of the VH chain MF3991 with up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably up to 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or combinations thereof relative to the VH chain sequence (preferably wherein the insertions, deletions, substitutions are not in the CDRl, CDR2 or CDR3). Optionally, they are also not in the FR4 region. Optionally, the amino acid substitutions are conservative amino acid substitutions

[0212] Optionally, the amino acid sequence of the ERBB3-specific heavy chain variable region VH chain MF3178 has up to 15, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably up to 1, 2, 3, 4, or 5 amino acid insertions, deletions, substitutions, or combinations thereof, relative to the VH chain sequence. These one or more amino acid insertions, deletions, substitutions, or combinations thereof are preferably not located in the CDR1, CDR2, or CDR3 regions of the VH chain. They are also preferably not present in the FR4 region. The amino acid substitutions are preferably conserved amino acid substitutions.

[0213] Optionally, the first antigen-binding site of the antibody comprises at least the CDR1, CDR2, and CDR3 sequences of MF3958, or has at most three, preferably at most two, and most preferably at most one CDR1, CDR2, and CDR3 sequences different from the CDR1, CDR2, and CDR3 sequences of MF3958, and wherein the second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of MF3178, or has at most three, preferably at most two, and most preferably at most one CDR1, CDR2, and CDR3 sequences different from the CDR1, CDR2, and CDR3 sequences of MF3178.

[0214] Optionally, the bispecific antibody comprises i) a first antigen-binding site comprising an ERBB2-specific heavy chain variable region and a light chain variable region, wherein the ERBB2-specific heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences of MF3958, and ii) a second antigen-binding site comprising an ERBB3-specific heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences of MF3178.

[0215] Optionally, the ERBB2-specific heavy chain variable region has the MF3958 sequence and the ERBB3-specific heavy chain variable region has the MF3178 sequence. This combination is also referred to as the PB4188 antibody. Preferably, the PB4188 antibody is unfucosylated.

[0216] Optionally, the bispecific antibody comprises, for example, Figure 3 The "heavy chain combined with ERBB2" shown in a and such Figure 3 The "heavy chain combined with ERBB3" shown in b.

[0217] Optionally, the antigen binding site of the bispecific antibody comprises a common light chain as defined herein, preferably a germline common light chain, preferably a rearranged germline human kappa light chain IgVK1-39*01 / IGJK1*01 or a fragment or functional derivative thereof (nomenclature according to IMGT database worldwide web imgt.org). The term rearranged germline human kappa light chain IgVK1-39*01 / IGJK1*01, IGKV1-39 / IGKJ1, huVK1-39 light chain or simply VK1-39 is used. The light chain can have 1, 2, 3, 4 or 5 amino acid insertions, deletions, substitutions or combinations thereof. Said 1, 2, 3, 4 or 5 amino acid substitutions are preferably conservative amino acid substitutions, insertions, deletions, substitutions or combinations thereof, preferably not in the CDR3 region of the VL chain, preferably not in the CDR1, CDR2 or CDR3 region or FR4 region of the VL chain. Preferably, the first and the second antigen binding site comprise the same light chain variable region, or a common light chain. Preferably, the light chain variable region comprises a CDR1 having the sequence (RASQSISSYLN), a CDR2 having the sequence (AASSLQS) and a CDR3 having the sequence (QQSYSTPPT), respectively QSISSY, AAS and QQSYSTPPT according to KABAT numbering or according to IMGT numbering system. Preferably, the light chain variable region comprises a CDR1 having the sequence (RASQSISSYLN), a CDR2 having the sequence (AASSLQS) and a CDR3 having the sequence (QQSYSTPPT), respectively QSISSY, AAS and QQSYSTPPT according to KABAT numbering or according to IMGT numbering system. Figure 1 a to 1f common light chain sequences.

[0218] Various methods can be used to produce bispecific antibodies and are discussed in WO 2015 / 130173. One of the methods involves expressing two different heavy chains and two different light chains in a cell and collecting the antibodies produced by the cell. Antibodies produced in this way will typically comprise a collection of antibodies with different combinations of heavy and light chains, some of which are the desired bispecific antibodies. The bispecific antibodies can then be purified from the collection.

[0219] The ratio of bispecific antibodies produced by the cells to other antibodies can be increased in various ways. Preferably, the ratio is increased by expressing two substantially identical light chains in the cells, rather than expressing two different light chains. This concept is also referred to in the art as the "common light chain" approach. When substantially identical light chains are used in conjunction with two different heavy chains, allowing the formation of variable domains with different antigen binding sites and accompanying different binding characteristics, the ratio of bispecific antibodies produced by the cells to other antibodies is significantly increased compared to the expression of two different light chains. The ratio of bispecific antibodies produced by the cells can be further increased by stimulating the pairing of two different heavy chains to each other, compared to the pairing of two identical heavy chains. Various methods to achieve such heavy chain heterodimerization are described in the art. One preferred method is described in PCT application no. PCT / NL2013 / 050294 (WO 2013 / 157954 Al), which is incorporated herein by reference. Methods and means are disclosed for the production of bispecific antibodies from a single cell, thereby providing means that favor the formation of bispecific antibodies over the formation of monospecific antibodies.

[0220] For the purposes of clarity and brevity, features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the application can include embodiments having all or some of the features described. Furthermore, any aspect disclosed herein in relation to any use in a method of treatment according to the application is equally applicable to the method of treatment of the application, and vice versa.

[0221] Clause

[0222] 1. A bispecific antibody comprising an antigen binding site that can bind to an extracellular part of ERBB2 and an antigen binding site that can bind to an extracellular part of ERBB3, for use in a method of treating castration-resistant prostate cancer in an individual.

[0223] 2. The bispecific antibody for use according to item 1, wherein the cancer has progressed after prior treatment with an androgen receptor axis-targeting agent.

[0224] 3. The bispecific antibody for use according to item 2, wherein the androgen receptor axis-targeting agent is an androgen receptor antagonist, such as a second-generation androgen receptor antagonist.

[0225] 4. The bispecific antibody for use according to item 3, wherein the androgen receptor antagonist is enzalutamide.

[0226] 5. The bispecific antibody for use according to item 2, wherein the androgen receptor axis-targeting agent is an androgen synthesis inhibitor, such as abiraterone acetate.

[0227] 6. The bispecific antibody for use of any of the preceding clauses, wherein the method of treatment further comprises use of an androgen receptor axis-targeting agent.

[0228] 7. The bispecific antibody for use of any of clauses 1 to 5, wherein the method of treatment further comprises use of an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, such as enzalutamide.

[0229] 8. The bispecific antibody for use of any of clauses 1 to 5, wherein the method of treatment further comprises use of an androgen synthesis inhibitor, such as abiraterone acetate.

[0230] 9. The bispecific antibody for use of any of clauses 1 to 4 or 6 to 7, wherein if the cancer has progressed after prior treatment with an androgen receptor antagonist, the method of treatment with the bispecific antibody further comprises use of an androgen receptor antagonist.

[0231] 10. The bispecific antibody for use of clause 9, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody are the same.

[0232] 11. The bispecific antibody for use or method of clauses 9 or 10, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody are both enzalutamide.

[0233] 12. The bispecific antibody for use of any of clauses 4, 7 or 11, wherein the enzalutamide is administered at 160 mg once a day.

[0234] 13. The bispecific antibody for use or method of any of clauses 1, 2, 5, 6 or 8, wherein if the cancer has progressed after prior treatment with an androgen synthesis inhibitor, the method of treatment with the bispecific antibody further comprises use of an androgen synthesis inhibitor.

[0235] 14. The bispecific antibody for use of clause 13, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment with the bispecific antibody are the same.

[0236] 15. The bispecific antibody for use according to item 13 or 14, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment with the bispecific antibody are both abiraterone acetate.

[0237] 16. The bispecific antibody for use according to any one of items 5, 8 or 15, wherein abiraterone acetate is administered at 1000 mg once a day.

[0238] 17. The bispecific antibody for use according to item 16, wherein abiraterone acetate is administered in combination with prednisone at 5 mg twice a day.

[0239]

[0240] 18. A method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual a bispecific antibody comprising an antigen- binding site that can bind an extracellular part of ERBB2 and an antigen-binding site that can bind an extracellular part of ERBB3.

[0241] 19. Use of a bispecific antibody comprising an antigen-binding site that can bind an extracellular part of ERBB2 and an antigen-binding site that can bind an extracellular part of ERBB3 for the manufacture of a medicament for the treatment of castration-resistant prostate cancer in an individual.

[0242] 20. The method of treatment or use according to item 18 or 19, wherein the cancer has progressed after prior treatment with an androgen receptor axis-targeting agent.

[0243] 21. The method of treatment or use according to item 20, wherein the androgen receptor axis- targeting agent is an androgen receptor antagonist, such as a second-generation androgen receptor antagonist.

[0244] 22. The method of treatment or use according to item 21, wherein the androgen receptor antagonist is enzalutamide.

[0245]

[0246] 23. The method of treatment or use according to item 20, wherein the androgen receptor axis- targeting agent is an androgen synthesis inhibitor, such as abiraterone acetate.

[0247] ​​24. The method of treatment or use of any one of clauses 18 to 23, wherein the treatment with the bispecific antibody or the use for the manufacture of a medicament further comprises administering or using an androgen receptor axis-targeting agent.

[0248] 25. The method of treatment or use of any one of clauses 18 to 23, wherein the treatment with the bispecific antibody or the use for the manufacture of a medicament further comprises administering or using an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, such as enzalutamide.

[0249] 26. The method of treatment or use of any one of clauses 18 to 23, wherein the treatment with the bispecific antibody or the use for the manufacture of a medicament further comprises administering or using an androgen synthesis inhibitor, such as abiraterone acetate.

[0250] 27. The method of treatment or use of any one of clauses 18 to 26, wherein if the cancer has progressed after prior treatment with an androgen receptor antagonist, wherein the method of treatment with the bispecific antibody or the use for the manufacture of a medicament further comprises administering or using an androgen receptor antagonist.

[0251] 28. The method of treatment or use of clause 27, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody or the use for the manufacture of a medicament are the same.

[0252] 29. The method of treatment or use of clause 27 or 28, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody or the use for the manufacture of a medicament are both enzalutamide.

[0253] 30. The method of treatment or use of any one of clauses 22, 25 or 29, wherein enzalutamide

[0254] is administered at 160 mg once a day.

[0255] 31. The method of treatment or use of any one of clauses 18, 19, 23, 24 or 26, wherein if the cancer has progressed after prior treatment with an androgen synthesis inhibitor, the method of treatment with the bispecific antibody or the use for the manufacture of a medicament further comprises administering or using an androgen synthesis inhibitor.

[0256] 32. The method of treatment or use of item 31, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment using the bispecific antibody or use for the manufacture of a medicament are the same.

[0257] 33. The method of treatment or use of item 31 or 32, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment using the bispecific antibody or use for the manufacture of a medicament are both abiraterone acetate.

[0258] 34. The method of treatment or use of any one of items 23, 26 or 33, wherein the abiraterone acetate is administered at 1000 mg once a day.

[0259]

[0260] 35. The method of treatment or use of item 34, wherein the abiraterone acetate is administered in combination with prednisone at 5 mg twice a day.

[0261] 36. The bispecific antibody for use of any one of items 1 to 17, or the method of treatment or use of any one of items 18 to 35, wherein the method of treatment comprises administering the bispecific antibody in an amount of 750

[0262] mg once every two weeks.

[0263] 37. The bispecific antibody for use of any one of items 1 to 17 or 36, or the method of treatment or use of any one of items 18 to 36, wherein the individual or cancer has a PTEN wild-type status.

[0264] 38. The bispecific antibody for use of any one of items 1 to 17 or 36, or the method of treatment or use of any one of items 18 to 36, wherein the individual or cancer does not exhibit a PTEN deletion.

[0265]

[0266] 39. The bispecific antibody for use of any one of items 1 to 17 or 36 to 38, or the method of treatment or use of any one of items 18 to 38, wherein the method of treatment comprises administering to an individual in need thereof a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3. ​​

[0267] 40. The bispecific antibody for use of any one of items 6 to 17 or 36 to 39, or the method of treatment or use of any one of items 24 to 39, wherein the androgen receptor axis-targeting agent is administered or to be administered according to a medical prescription as indicated by a health authority such as the FDA.

[0268] 41. The bispecific antibody for use of any one of items 1 to 17 or 36 to 40, or the method of treatment or use of any one of items 18 to 40, wherein the cancer is characterized by histologically confirmed prostate adenocarcinoma, which optionally does not have neuroendocrine differentiation or small cell features.

[0269] 41. The bispecific antibody for use of any one of items 1 to 17 or 36 to 40, or the method of treatment or use of any one of items 18 to 40, wherein the cancer is characterized by histologically confirmed prostate adenocarcinoma, which optionally does not have neuroendocrine differentiation or small cell features.

[0270] 42. The bispecific antibody for use of any one of items 1 to 17 or 36 to 41, or the method of treatment or use of any one of items 18 to 41, wherein the bispecific antibody comprises a first antigen-binding site that can bind to domain I of ERBB2, and a second antigen-binding site that can bind to domain III of ERBB3.

[0271] 43. The bispecific antibody for use of any one of items 1 to 17 or 36 to 42, or the method of treatment or use of any one of items 18 to 42, wherein the bispecific antibody comprises

[0272] i) at least CDR1, CDR2 and CDR3 sequences in an ERBB2-specific heavy chain variable region selected from the group consisting of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 and MF3003, or wherein the antibody comprises CDR sequences that differ by at most 3 amino acids, preferably at most 2 amino acids, preferably at most 1 amino acid from the CDR1, CDR2 and CDR3 sequences of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 or MF3003; and / or

[0273] ii) at least CDR1, CDR2 and CDR3 sequences in an ERBB3-specific heavy chain variable region selected from the group consisting of MF3178; MF3176;

[0274] MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; and MF6074, or wherein the antibody comprises CDR sequences that differ by up to 3 amino acids, preferably up to 2 amino acids, preferably up to 1 amino acid from the CDR1, CDR2, and CDR3 sequences of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; or MF6074.

[0275] 44. The bispecific antibody for use of any one of items 1 to 17, or 36 to 43, or the method of treatment or use of any one of items 18 to 43, wherein the bispecific antibody comprises

[0276] i) an ERBB2-specific heavy chain variable region sequence selected from the group consisting of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, and MF3003, or wherein the antibody comprises a heavy chain variable region sequence that differs by up to 15 amino acids from the heavy chain variable region sequence of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, or MF3003; and / or

[0277] ii) an ERBB3-specific heavy chain variable region sequence selected from the group consisting of: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; and MF6074, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; or MF6074 by up to 15 amino acids.

[0278] 45. The bispecific antibody for use of any of items 1 to 17, or 36 to 44, or the method of treatment or use of any of items 18 to 44, wherein the bispecific antibody comprises the heavy chain variable regions of MF3958 and MF3178.

[0279] 46. The bispecific antibody for use of any of items 1 to 17, or 36 to 45, or the method of treatment or use of any of items 18 to 45, wherein the bispecific antibody comprises a variable domain comprising the first antigen binding site and a variable domain comprising the second antigen binding site, and wherein the first and second antigen binding sites comprise a light chain variable region comprising a CDR1 comprising the sequence QSISSY, a CDR2 comprising the sequence AAS, and a CDR3 comprising the sequence QQSYSTPPT.

[0280] QQSYSTPPT.

[0281] 47. An antibody comprising an antigen binding site that can bind to an extracellular part of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual.

[0282] 48. A method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual a therapeutically effective amount of an antibody comprising an antigen binding site that can bind to an extracellular part of ERBB3.

[0283] 47. An antibody comprising an antigen binding site that can bind to an extracellular part of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual.

[0284] 49. Use of an antibody comprising an antigen binding site that can bind to an extracellular portion of ERBB3 in the manufacture of a medicament for treating castration-resistant prostate cancer in an individual.

[0285] 50. The antibody for use of clause 47, the method of treatment of clause 48, or the use of clause 49, wherein the antibody comprises an antigen binding site that binds to domain III of ERBB3.

[0286] 51. The antibody for use of clause 47 or 50, the method of treatment of clause 48 or 50, or the use of clause 49 or 50, wherein the antibody comprises

[0287] i) at least CDR1, CDR2 and CDR3 sequences in an ERBB3-specific heavy chain variable region selected from the group consisting of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or wherein the antibody comprises CDR sequences that differ by at most 3 amino acids, preferably at most 2 amino acids, preferably at most 1 amino acid from the CDR1, CDR2 and CDR3 sequences of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074.

[0288] 52. The antibody for use of clause 47 or any one of clauses 50 to 51, the method of treatment of clause 48 or any one of clauses 50 to 51, or the use of any one of clauses 49 to 51, wherein the antibody comprises

[0289] i) an ERBB3-specific heavy chain variable region sequence selected from the group consisting of: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; and MF6074, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073; or MF6074 by up to 15 amino acids.

[0290] 53. The antibody for use of any one of clauses 47 or 50-52, the treatment method of any one of clauses 48 or 50-52, or the use of any one of clauses 49-52, wherein the antibody comprises a heavy chain variable region of MF3178.

[0291] 54. The antibody for use of any one of clauses 47 or 50-53, the treatment method of any one of clauses 48 or 50-53, or the use of any one of clauses 49-53, wherein the antibody comprises a variable domain comprising an antigen binding site capable of binding to an extracellular portion of ERBB3, and wherein the antigen binding site comprises a light chain variable region comprising a CDR1 comprising the sequence QSISSY, a CDR2 comprising the sequence AAS, and a CDR3 comprising the sequence QQSYSTPPT.

[0292] QSISSY, a CDR2 comprising the sequence AAS, and a CDR3 comprising the sequence QQSYSTPPT.

[0293] 55. The antibody for use of any one of clauses 47 or 50-54, the treatment method of any one of clauses 48 or 50-54, or the use of any one of clauses 49-54, wherein the antibody is a monospecific antibody, such as a monospecific bivalent antibody, that binds to ERBB3.

[0294] 56. The antibody for use of any one of items 47 or 50 to 55, the method of treatment of any one of item 48 or 50 to 55, or the use of any one of items 49 to 55, wherein the antibody comprises patritumab (U3- -1287 / A888), seribantumab (MM-121), lumretuzumab (RG7116, RO-5479599), elgemtumab (LJM716), AV-203, KTN3379 / CDX-3379, GSK2849330, or an antibody-drug conjugate such as patritumab deruxtecan (U3- -1402).

[0295] (seribantumab) (MM-121), lumretuzumab (RG7116,

[0296] RO-5479599), elgemtumab (LJM716), AV-203,

[0297] KTN3379 / CDX-3379, GSK2849330, or an antibody-drug conjugate such as patritumab deruxtecan (U3- -1402).

[0298] 57. The antibody for use of any one of items 47 or 50 to 55, the method of treatment of any one of item 48 or 50 to 55, or the use of any one of items 49 to 55, wherein the antibody can reduce or reduces ligand-induced receptor function of ERBB3.

[0299] 58. The antibody for use of any one of items 47 or 50 to 55, the method of treatment of any one of item 48 or 50 to 55, or the use of any one of items 49 to 55, wherein the antibody comprises an antigen binding site that can bind to an extracellular part of ERBB3, which blocks ERBB3 and its ligand heregulin.

[0300] 59. The antibody for use of any one of items 47 or 50 to 58, the method of treatment of any one of item 48 or 50 to 58, or the use of any one of items 49 to 58, wherein the cancer has progressed after prior treatment with an androgen receptor axis-targeting agent.

[0301] 60. The antibody for use of item 59, the method of treatment of item 59, or the use of item 59, wherein the androgen receptor axis-targeting agent is an androgen receptor antagonist, such as a second-generation androgen receptor antagonist.

[0302] 61. The antibody for use of item 60, the method of treatment of item 60, or the use of item 60, wherein the androgen receptor antagonist is enzalutamide.

[0303] 62. The antibody for use of item 59, the treatment method of item 59, or the use of item 59, wherein the androgen receptor axis-targeting agent is an androgen synthesis inhibitor, such as abiraterone acetate.

[0304] 63. The antibody for use of any one of items 47 or 50-62, the treatment method of any one of item 48 or 50-62, or the use of any one of items 49-62, wherein the treatment method further comprises using an androgen receptor axis-targeting agent.

[0305] 64. The antibody for use of any one of items 47 or 50-62, the treatment method of any one of item 48 or 50-62, or the use of any one of items 49-62, wherein the treatment method further comprises using an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, such as enzalutamide.

[0306] 65. The antibody for use of any one of items 47 or 50-62, the treatment method of any one of item 48 or 50-62, or the use of any one of items 49-62, wherein the treatment method further comprises using an androgen synthesis inhibitor, such as abiraterone acetate.

[0307] 66. The antibody for use of any one of items 47, 50-61, or 63-64, the treatment method of any one of item 48, 50-61, or 63-64, or the use of any one of items 49-61, or 63-64, wherein if the cancer has progressed after prior treatment with an androgen receptor antagonist, the treatment method using the bispecific antibody further comprises using an androgen receptor antagonist.

[0308] 67. The antibody for use of item 66, the treatment method of item 66, or the use of item 66, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the treatment method using the bispecific antibody are the same.

[0309] 68. The antibody for use of item 66 or 67, the treatment method of item 66 or 67, or the use of item 66 or 67, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the treatment method using the bispecific antibody are both enzalutamide.

[0310] 69. The antibody for use of any one of items 61, 64, or 68, the treatment method of any one of items 61, 64, or 68, or the use of any one of items 61, 64, or 68, wherein enzalutamide is administered at 160 mg once a day.

[0311] 70. The antibody for use of any one of items 47 or 50 to 59, 62, 63, or 65, the treatment method of any one of items 48 or 50 to 59, 62, 63, or 65, or the use of any one of items 49 to 59, 62, 63, or 65, wherein the treatment method using the bispecific antibody further comprises use of an androgen synthesis inhibitor if the cancer has progressed after prior treatment with an androgen synthesis inhibitor.

[0312] 71. The antibody for use of item 70, the treatment method of item 70, or the use of item 70, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the treatment method using the bispecific antibody are the same.

[0313] 72. The antibody for use of item 70 or 71, the treatment method of item 70 or 71, or the use of item 70 or 71, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the treatment method using the bispecific antibody are both abiraterone acetate.

[0314] 73. The antibody for use of any one of items 62, 65, or 72, the treatment method of any one of items 62, 65, or 72, or the use of any one of items 62, 65, or 72, wherein abiraterone acetate is administered at 1000 mg once a day.

[0315] 74. The antibody for use of item 73, the treatment method of item 73, or the use of item 73, wherein abiraterone acetate is administered in combination with prednisone at 5 mg twice a day.

[0316] 75. The antibody for use of any one of items 47 or 50 to 74, the treatment method of any one of items 48 or 50 to 74, or the use of any one of items 49 to 74, wherein the treatment method comprises administration of the bispecific antibody at a quantity of 750 mg once every two weeks.

[0317] 76. The antibody for use of any one of items 47 or 50 to 75, the treatment method of any one of item 48 or 50 to 75, or the use of any one of items 49 to 75, wherein the individual or cancer has a PTEN wild-type status.

[0318] 77. The antibody for use of any one of items 47 or 50 to 76, the treatment method of any one of item 48 or 50 to 76, or the use of any one of items 49 to 76, wherein the individual or cancer does not exhibit a PTEN deletion.

[0319] 78. The antibody for use of any one of items 47 or 50 to 77, the treatment method of any one of item 48 or 50 to 77, or the use of any one of items 49 to 77, wherein the treatment method comprises administering to an individual in need thereof a therapeutically effective amount of the antibody.

[0320] 79. The antibody for use of any one of items 47 or 50 to 78, the treatment method of any one of item 48 or 50 to 78, or the use of any one of items 49 to 78, wherein the androgen receptor axis-targeting agent is administered or to be administered according to a medical prescription as indicated by a health authority such as the FDA.

[0321] 80. The antibody for use of any one of items 47 or 50 to 79, the treatment method of any one of item 48 or 50 to 79, or the use of any one of items 49 to 79, wherein the cancer is characterized by a histologically confirmed prostate adenocarcinoma, which optionally does not have neuroendocrine differentiation or small cell features.

[0322] 81. A method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting the individual for said treatment if the sample does not exhibit a PTEN deletion.

[0323] 82. A method of establishing whether an individual having castration-resistant prostate cancer is likely to respond to treatment with a bispecific antibody comprising an antigen- binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or to treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) selecting a sample that does not exhibit a PTEN deletion, thereby establishing that the individual from which the sample was derived is likely to respond to the treatment.

[0324] 83. A method of classifying an individual having castration-resistant prostate cancer based on the PTEN status prior to treatment with a bispecific antibody comprising an antigen- binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or prior to treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the PTEN status in a sample obtained from the individual; b) classifying the individual from which the sample was derived as eligible for the treatment if the sample does not exhibit a PTEN deletion.

[0325] 84. The method of any one of claims 81-83, wherein the PTEN status is determined using IHC.

[0326] 85. The method of any one of claims 81-83, wherein the PTEN status is determined using a liquid biospecimen.

[0327] 86. A kit-of-parts comprising a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 and an androgen receptor axis-targeting agent.

[0328] 87. The kit-of-parts of claim 86, further comprising instructions for use.

[0329] 88. The kit-of-parts of claim 86 or 87, wherein the instructions for use comprise instructions for administering the bispecific antibody and the androgen receptor axis-targeting agent.

[0330] 89. The kit-of-parts of any one of claims 86-88, wherein the androgen receptor axis- targeting agent comprises an androgen receptor antagonist such as a second-generation androgen receptor antagonist such as enzalutamide, or an androgen synthesis inhibitor such as abiraterone acetate, and wherein the bispecific antibody comprises zenocutuzumab.

[0331] 90. The kit-of-parts of item 89, wherein the instructions comprise administration of 1000 mg of abiraterone acetate once a day in combination with 5 mg of prednisone twice a day, and administration of the bispecific antibody once every two weeks in an amount of 750 mg.

[0332] 91. The kit-of-parts of item 89, wherein the instructions comprise administration of 160 mg of enzalutamide once a day and administration of the bispecific antibody once every two weeks in an amount of 750 mg.

[0333] 92. The kit-of-parts of item 90 or 91, wherein the instructions for the abiraterone acetate or enzalutamide comprise instructions for oral administration, and the administration of the bispecific antibody comprises instructions for intravenous injection.

[0334] 93. A kit-of-parts comprising an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3 and an androgen receptor axis-targeting agent.

[0335] 94. The kit-of-parts of item 93, further comprising instructions for use.

[0336] 95. The kit-of-parts of item 93 or 94, wherein the instructions comprise instructions for administration of the antibody and the androgen receptor axis-targeting agent.

[0337] 96. The kit-of-parts of any one of items 93 to 95, wherein the androgen receptor axis-targeting agent comprises an androgen receptor antagonist such as a second-generation androgen receptor antagonist such as enzalutamide, or comprises an androgen synthesis inhibitor such as abiraterone acetate, and wherein the antibody comprises zenocutuzumab.

[0338] 97. The kit-of-parts of item 96, wherein the instructions comprise administration of 1000 mg of abiraterone acetate once a day in combination with 5 mg of prednisone twice a day, and administration of the antibody once every two weeks in an amount of 750 mg.

[0339] 98. The kit-of-parts of item 96, wherein the instructions comprise administration of 160 mg of enzalutamide once a day and administration of the antibody once every two weeks in an amount of 750 mg.

[0340] 99. The kit-of-parts of item 97 or 98, wherein the instructions for the abiraterone acetate or enzalutamide comprise instructions for oral administration, and the administration of the antibody comprises instructions for intravenous injection.

[0341] 100. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer has a PTEN loss status.

[0342] 101. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer exhibits a PTEN loss.

[0343] 102. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer does not have a oncogenic driver mutation in any of the PI3K, AKT, and / or mTOR pathways, or wherein the individual or cancer does not have upregulation of any of the pathways.

[0344] 103. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer does not exhibit a oncogenic driver mutation in any of the PI3K,

[0345] AKT, and / or mTOR pathways, or wherein the individual or cancer does not exhibit upregulation of any of the pathways.

[0346] 104. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer does not have a oncogenic driver mutation in any of the known tumor-associated genes or proteins encoded thereby, such as EGFR, cMET, ALK, BRAF,

[0347] KRAS, NRAS, RET, and ROS1.

[0348] 105. The bispecific antibody for use of any of items 1-17 or 36, the treatment method or use of any of items 18-36, wherein the individual or cancer does not exhibit a oncogenic driver mutation in any of the known tumor-associated genes or proteins encoded thereby, such as EGFR, cMET, ALK, BRAF,

[0349] KRAS, NRAS, RET, and ROS1.

[0350] 106. The bispecific antibody for use of item 47 or any of items 50-75, the treatment method of item 48 or any of items 50-75, or the use of any of items 49-75, wherein the individual or cancer has a PTEN loss status.

[0351] 107. The bispecific antibody for use of any one of items 47 or 50-75, the treatment method of any one of item 48 or 50-75, or the use of any one of items 49-75, wherein the individual or cancer exhibits a PTEN deletion.

[0352] 108. The bispecific antibody for use of any one of items 47 or 50-75, the treatment method of any one of item 48 or 50-75, or the use of any one of items 49-75, wherein the individual or cancer does not have an oncogenic driver mutation in any known tumor-associated gene or protein encoded thereby, such as EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1.

[0353] 109. The bispecific antibody for use of any one of items 47 or 50-75, the treatment method of any one of item 48 or 50-75, or the use of any one of items 49-75, wherein the individual or cancer does not exhibit an oncogenic driver mutation in any known tumor-associated gene or protein encoded thereby, such as EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1.

[0354] 110. A method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the presence of an oncogenic driver mutation of any of the PI3K, AKT, and / or mTOR pathway or a mutation that modulates the PI3K, AKT, and / or mTOR pathway in a sample obtained from the cancer of the individual; and b) selecting the individual for the treatment if the sample lacks an oncogenic driver mutation in the PI3K, AKT, and / or mTOR pathway or lacks a mutation that modulates the PI3K, AKT, and / or mTOR pathway.

[0355] mTOR pathway.

[0356] 111. The method of item 110, wherein the cancer of the individual is determined by next- generation sequencing, such as DNA, RNA, or whole transcriptome sequencing.

[0357] 112. A method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) determining the presence of a oncogenic driver mutation in any of the EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1 pathways in a sample obtained from the individual's cancer; b) selecting the individual for the treatment if the sample lacks the oncogenic driver mutation.

[0358] 113. The method of item 110, wherein the individual's cancer is determined by next generation sequencing, such as DNA, RNA, or whole transcriptome sequencing.

[0359] 114. A method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) testing the individual's cancer by next generation sequencing to determine whether a sample obtained from the individual has a oncogenic driver mutation that modulates any of the PI3K, AKT, and / or mTOR pathways; b) classifying the individual from which the sample was obtained as eligible for the treatment if the sample lacks the oncogenic driver mutation.

[0360] 115. A method of selecting an individual having castration-resistant prostate cancer for treatment with a bispecific antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB2 and an antigen-binding site that can bind an extracellular portion of ERBB3 or treatment with an antibody comprising an antigen-binding site that can bind an extracellular portion of ERBB3, the method comprising: a) testing the individual's cancer by next generation sequencing to determine whether a sample obtained from the individual has a oncogenic driver mutation, optionally, in any of EGFR, cMET, ALK, BRAF, KRAS, NRAS, RET, and ROS1; b) classifying the individual from which the sample was obtained as eligible for the treatment if the sample lacks the oncogenic driver mutation.

[0361] 116. The method of any one of items 110 to 115, wherein the individual or cancer further has a wild-type PTEN status.

[0362] Examples

[0363] "MFXXXX" (where X is independently a number 0 to 9) as used herein refers to a Fab comprising variable domains, wherein the VH has the amino acid sequence identified by the 4 digits Figure 3 a to 3b. The light chain variable region of the variable domains generally has the sequence of Figure 1 b, unless indicated otherwise. The light chain in the examples has the sequence as indicated by Figure 1 c. "MFXXXX VH" refers to the amino acid sequence of the VH identified by the 4 digits. MF further comprises the constant region of the light chain, and the constant region of the heavy chain, which generally interacts with the constant region of the light chain. The VH / variable region of the heavy chain is different and generally also the CH3 region, wherein one of the heavy chains has a KK mutation of its CH3 domain, and the other has a complementary DE mutation of its CH3 domain (see references PCT / NL2013 / 050294 (published as WO2013 / 157954), and Figure 2 d and Figure 2 e). The bispecific antibodies in the examples have an Fc tail with KK / DE CH3 heterodimerization domains, CH2 domains and CH1 domains as indicated by Figure 2 a to 2e, a common light chain as indicated by Figure 1 a, and VH as indicated by the MF number. Example 1: a multispecific antibody binding domain I of ERBB2 and domain III of ERBB3.

[0364] Bispecific antibodies comprising the heavy chain variable regions mentioned in Table 2 and Table 3 are obtained as described in WO2015 / 130173. The shown ERBB3 binding domains can also be used to provide monospecific antibodies.

[0365] ERBB2 binding domain ID SEQ ID NO ERBB3 binding domain ID SEQ ID NO MF2973 SEQ ID NO: 2 MF3178 SEQ ID NO: 47 MF3004 SEQ ID NO: 7 MF3176 SEQ ID NO: 52 MF3958 SEQ ID NO: 12 MF3163 SEQ ID NO: 57 MF2971 SEQ ID NO: 17 MF6055 SEQ ID NO: 62 MF3025 SEQ ID NO: 22 MF6056 SEQ ID NO: 67 MF2916 SEQ ID NO: 27 MF6057 SEQ ID NO: 72 MF3991 SEQ ID NO: 32 MF6058 SEQ ID NO: 77 MF3031 SEQ ID NO: 37 MF6059 SEQ ID NO: 82 MF3003 SEQ ID NO: 42 MF6060 SEQ ID NO: 87 MF6061 SEQ ID NO: 92 MF6062 SEQ ID NO: 97 MF6063 SEQ ID NO: 102 MF6064 SEQ ID NO: 107 MF6065 SEQ ID NO: 112 MF6066 SEQ ID NO: 117 MF6067 SEQ ID NO: 122 MF6068 SEQ ID NO: 127 MF6069 SEQ ID NO: 132 MF6070 SEQ ID NO: 137 MF6071 SEQ ID NO: 142 MF6072 SEQ ID NO: 147

[0366] Table 2: SEQ ID NO's of heavy chain variable regions of bispecific antibodies binding ERBB2 and ERBB3.

[0367] MF2973 MF3004 MF3958 MF2971 MF3025 MF2916 MF3991 MF3031 MF3003 MF3178 X X X X X X X X X MF3176 X X X X X X X X X MF3163 X X X X X X X X X MF6055 X X X X X X X X X MF6056 X X X X X X X X X MF6057 X X X X X X X X X MF6058 X X X X X X X X X MF6059 X X X X X X X X X MF6060 X X X X X X X X X MF6061 X X X X X X X X X MF6062 X X X X X X X X X MF6063 X X X X X X X X X MF6064 X X X X X X X X X MF6065 X X X X X X X X X MF6066 X X X X X X X X X MF6067 X X X X X X X X X MF6068 X X X X X X X X X MF6069 X X X X X X X X X MF6070 X X X X X X X X X MF6071 X X X X X X X X X MF6072 X X X X X X X X X MF6073 X X X X X X X X X MF6074 X X X X X X X X X

[0368] Table 3: any of the heavy chain variable regions binding ERBB2 can be combined with any of the heavy chain variable regions binding ERBB3 in the bispecific antibodies of the application. Variants of this variable heavy chain region can also be combined in the bispecific antibodies of the application.

[0369] Example 2:

[0370] A clinical study of zenocutuzumab (a full length IgGl bispecific antibody comprising MF3958 x MF3178, targeting ERBB2 and ERBB3) in patients with castration resistant prostate cancer.

[0371] This is a Phase II, open-label, multi-center international study to evaluate the efficacy of zenocutuzumab in patients with metastatic mCRPC who have evidence of disease progression by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria on the last prior hormonal therapy including a second-generation AR antagonist enzalutamide, or androgen synthesis inhibitor abiraterone acetate. Patients will be enrolled and will receive combination treatment of zenocutuzumab with an AR-targeted agent, they have experienced disease progression prior to entering the study. A cohort of patients with wild-type status of phosphatase and tensin homolog (PTEN) will be enrolled. Safety evaluation readiness will be performed on the first 4 to 6 patients.

[0372] Study Drug

[0373] Zenocutuzumab is an investigational medicinal product, the concomitant AR signaling inhibitor is considered a non-investigational medicinal product. Zenocutuzumab, a bispecific humanized full-length IgGl antibody, is formulated at 20 mg / mL.

[0374] Zenocutuzumab (Zenocutuzumab)

[0375] Zenocutuzumab will be administered as a 2-hour IV infusion on Day 1, then Q2W for every 28-day cycle. A fixed dose of 750 mg will be administered.

[0376] Patients will receive zenocutuzumab in combination with other drugs. Prior to each infusion of zenocutuzumab, premedication is required. The mandatory premedication regimen is:

[0377] • Paracetamol / Acetaminophen 1000 mg PO or IV.

[0378] • Dexchlorpheniramine 5 mg IV (or other anti-Hl equivalent, PO or IV). • Dexamethasone 10 mg IV (or equivalent, PO or IV). Corticosteroids are mandatory only prior to the first infusion in Cycle 1 and should be at the discretion of the investigator for subsequent injections to manage infusion-related reactions (IRRs).

[0379] • The use of H2 antagonists is at the discretion of the investigator and can be given at the investigator’s judgment.

[0380] Next-generation AR signaling inhibitors

[0381] Patients will receive zenocutuzumab in combination with one of the following next-generation AR signaling inhibitors (the patient has received prior to entering the study):

[0382] • abiraterone acetate 1000 mg PO QD in combination with prednisone 5 mg PO twice daily (BID).

[0383] • enzalutamide 160 mg PO QD.

[0384] Administration of enzalutamide or abiraterone acetate will begin on Day 1 of Cycle 1.

[0385] Abiraterone acetate: Abiraterone acetate is taken in combination with prednisone and should be taken on an empty stomach. No food should be taken within at least 2 hours before and at least 1 hour after taking the medication. The tablets should be swallowed whole with water. Abiraterone acetate is available as 250-mg tablets, white to off-white, oval, one side concave, imprinted with AA 250. The tablets should be stored at 20°C to 25°C (68°F-77°F); excursions are permitted to 15°C to 30°C (59°F-86°F).

[0386] Enzalutamide: Enzalutamide can be taken with or without food. The capsules should be swallowed whole. Enzalutamide is available as 40-mg white to off-white, oblong, soft gelatin capsules, imprinted with black ink “MDV”. The capsules should be stored at 20°C to 25°C (68°F-77°F) in a dry place; excursions are permitted to 15°C to 30°C (59°F-86°F).

[0387] Treatment Adapations

[0388] Next-generation AR signaling inhibitors will be administered according to the local prescribing information for each drug. Dose adjustments of enzalutamide or abiraterone acetate are permitted based on clinical judgment of drug-related toxicities:

[0389] Abiraterone acetate: For patients who develop liver toxicity (ALT and / or AST greater than 5 x ULN or total bilirubin greater than 3 x ULN) during treatment, treatment should be discontinued. Once liver function tests return to the patient’s baseline or ALT and AST values < 2.5 x ULN and total bilirubin is < 1.5 x ULN, treatment can be restarted at a reduced dose of 750 mg QD. Once the patient resumes treatment, serum transaminases and bilirubin should be monitored at least every two weeks for 3 months and then monthly thereafter. If liver toxicity reoccurs at the 750 mg QD dose, treatment can be restarted at a reduced dose of 500 mg QD once function tests return to the patient’s baseline or ALT and AST < 2.5 x ULN and total bilirubin < 1.5 x ULN. If liver toxicity reoccurs after the dose is reduced to 500 mg QD, treatment should be discontinued.

[0390] Enzalutamide: If a patient experiences a Grade >3 toxicity or intolerable side effects, dosing is suspended for 1 week or until symptoms improve to Grade <2, after which dosing is resumed at the same or reduced dose (120 or 80 mg), if warranted.

[0391] Treatment discontinuation

[0392] Zanaburimab will be administered until any of the following occur, at which point it will be definitively discontinued, unless in the event of perceived benefit with sponsor concurrence. If there is a benefit event, whether to continue single agent treatment will be discussed on a case-by-case basis and agreed with the sponsor.

[0393] • Disease progression.

[0394] • AE / Unacceptable toxicity.

[0395] • Withdrawal of consent.

[0396] • Patient non-compliance.

[0397] • Investigator’s decision (e.g., clinical deterioration).

[0398] • Treatment interruption >6 consecutive weeks.

[0399] • Discontinuation of any treatment combination drug.

[0400] Eligible patients will be enrolled and will receive consecutive treatment cycles, with a treatment cycle being 4 weeks (28 days). All patients will receive a fixed dose of 750 mg of zanaburimab IV Q2W.

[0401] Study population

[0402] Inclusion criteria

[0403] Patients must meet all of the following requirements to enter the study:

[0404] 1. Sign an informed consent form prior to any study procedures.

[0405] 2. Be >18 years of age at the time of signing the informed consent form.

[0406] 3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0407] 4. Have a life expectancy of >12 weeks.

[0408] 5. At least 3 weeks since any major surgery, completion of radiation therapy, completion of all prior systemic anticancer therapy, or at least 5 half-lives if prior therapy was a single agent small molecule therapeutic drug, and fully recovered from acute toxicities of any prior therapy, to National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 Grade < 1, with the exception of alopecia or neuropathy.

[0409] 6. Left ventricular ejection fraction (LVEF) > 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) testing.

[0410] 7. Adequate organ function:

[0411] • Absolute neutrophil count > 1.5 x 10 9 / L.

[0412] • Hemoglobin > 9 g / dL.

[0413] • Platelets > 100 x 10 9 / L.

[0414] • Serum calcium within normal range (or corrected with supplementation).

[0415] • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 2.5 x

[0416] upper limit of normal (ULN) (if malignancy involves the liver, then ALT / AST < 5 x

[0417] ULN is allowed).

[0418] • Total bilirubin < 1.5 x ULN (if Gilbert’s disease, then total bilirubin < 3

[0419] x ULN is allowed).

[0420] • Estimated glomerular filtration rate > 30 mL / min according to Cockroft-Gault formula.

[0421] • Serum albumin > 3.0 g / dL.

[0422] 8. Representative tumor sample, either a fresh-frozen paraffin-embedded (FFPE) tumor specimen obtained de novo (i.e., within 2 months prior to signing the informed consent form) or a FFPE archival tumor sample (preferably collected within 2 years of the start of study treatment). Fresh FFPE sample is preferred.

[0423] 9. Sexually active male and female patients of childbearing potential must agree to use one of the following highly effective methods of contraception throughout the study period and for 6 months after the last dose of zanaburimab:

[0424] • Combination (estrogen and progestogen) hormonal contraceptives associated with inhibition of ovulation: oral, intravaginal, transdermal.

[0425] • Progestogen-only hormonal contraceptives associated with inhibition of ovulation: oral, injectable, implantable, intrauterine device, intrauterine hormone releasing system, bilateral occlusion of the fallopian tubes, partner vasectomy, sexual abstinence.

[0426] Further inclusion criteria: Patients must meet all of the following requirements to be enrolled in the study:

[0427] B1. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.

[0428] B2. Metastatic disease with at least 2 bone lesions documented on whole-body bone scan or soft tissue disease documented on computed tomography (CT) scan / magnetic resonance imaging (MRI).

[0429] B3. Continuous androgen deprivation and serum testosterone levels < 1.73 nmol / L (< 50 ng / dL) at screening and prior to treatment initiation.

[0430] B4. Current treatment with next-generation AR signaling inhibitors (enzalutamide or abiraterone) that started at least 90 days prior to screening and prior to treatment initiation. A maximum of 30 days of drug interruption is allowed prior to resumption of medication.

[0431] B5. According to PCWG3 study entry criteria, progressive disease is defined as one of the following:

[0432] • Prostate-specific antigen (PSA) progression defined as two consecutive increases in PSA from a prior reference value to a minimum of > 1 ng / mL prior to screening and treatment initiation (if the patient had > 14 days of abiraterone or enzalutamide drug interruption, the elevated PSA must be documented after resumption of medication).

[0433] • Soft tissue disease progression defined by RECIST v1.1.

[0434] • Lymph nodes that were previously normal (< 10 mm) must grow by > 5 mm in short axis to be considered as having progressed.

[0435] • Bone disease progression defined by > 2 new lesions on whole-body bone scan.

[0436] B6. Patients receiving bisphosphonate or denosumab therapy for bone health must be on a stable dose for at least 4 weeks prior to initiation of study treatment.

[0437] B7. Able to swallow oral medications and absence of gastrointestinal disease that is considered to compromise intestinal absorption (e.g., malabsorption, resection).

[0438] Exclusion Criteria

[0439] Exclusion criteria are the presence of any of the following criteria that would exclude a patient from participating in the study:

[0440] 1. Untreated or symptomatic central nervous system metastases, or the need for radiation, surgery, or ongoing steroid treatment to control symptoms within 14 days of study entry.

[0441] 2. Prior receipt of an anti-ERBB3-directed therapy.

[0442] 3. Known involvement of the leptomeninges.

[0443] 4. Participation in another interventional clinical trial or treatment with any study drug within 4 weeks prior to study entry.

[0444] 5. Long-term treatment with high-dose oral corticosteroids (>10 mg prednisone equivalent per day).

[0445] 6. Uncontrolled hypertension (systolic blood pressure >150 mm Hg and / or diastolic blood pressure >100 mm Hg) or unstable angina pectoris.

[0446] 7. History of New York Heart Association Class II-IV congestive heart failure or serious cardiac arrhythmias requiring treatment (except atrial fibrillation or paroxysmal supraventricular tachycardia).

[0447] 8. History of myocardial infarction within 6 months of study entry.

[0448] 9. History of prior or concomitant malignancy (except for resected non-melanoma skin cancer, cured carcinoma in situ of the cervix, or low-grade Ta or Tl urothelial carcinoma of the bladder that has received potentially curative treatment) within 3 years of study entry.

[0449] 10. Current presence of serious illness or health conditions, including but not limited to: uncontrolled active infection, and clinically significant pulmonary, metabolic, or psychiatric disease.

[0450] 11. Patients with the following known infectious diseases:

[0451] • Known active hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) but not receiving antiviral treatment. Note: Patients with active hepatitis B (HBsAg positive) must receive antiviral treatment with lamivudine, tenofovir, entecavir, or other antiviral medication at least > 7 days prior to start of study treatment. Patients with a history of hepatitis B (anti-HBc positive, HBsAg and hepatitis B virus [HBV] DNA negative) are eligible.

[0452] 12. Known human immunodeficiency virus (HIV)-positive patients, unless CD4+ count is > 300 / μL, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy.

[0453] Further exclusion criteria are the presence of any of the following criteria that would exclude a patient from participating in the study:

[0454] 13. More than 2 second-generation hormonal drugs for the treatment of metastatic disease.

[0455] 14. More than 2 systemic chemotherapies for metastatic disease.

[0456] 15. Patients with measurable disease only outside of bone metastases (e.g., pleural effusion, ascites, other internal organs).

[0457] 16. Patients receiving enzalutamide have a history of seizures or any condition that induces seizures in patients, including a history of loss of consciousness of unknown origin or transient ischemic attack within 12 months prior to study treatment.

[0458] Management of infusion-related reactions

[0459] Patients will be closely monitored during study treatment. Prior to each infusion of zanoximab, patients must premedicate with antihistamines, acetaminophen / paracetamol, and corticosteroids.

[0460] Prophylactic medications and concomitant medications

[0461] Allowed medications

[0462] • All medications required for the patient's health will be given by the investigator as deemed appropriate and not expected to interfere with the evaluation of study drug, including supportive treatment of symptoms and AEs, or standard treatment of concomitant conditions.

[0463] Luteinizing hormone-releasing hormone (LHRH) agonists or antagonists are allowed in patients who have not undergone prior bilateral resection.

[0464] Contraindicated medications

[0465] • Concurrent long-term oral corticosteroids (>10 mg / day prednisone equivalent), tumor necrosis factor (TNF)-alpha inhibitors, anti-T cell antibodies (due to risk of immunosuppression).

[0466] • Any study drug within 4 weeks prior to the first dose of study treatment.

[0467] • Patients should preferably not start a new study drug at least 4 weeks after the last dose of study drug. • Systemic anticancer therapy. Note: For patients in Cohort B, it is allowed that patients receive next-generation AR signaling inhibitors immediately prior to entering the study.

[0468] Efficacy assessments: Response measures, tumor measurements

[0469] Radiologic measurements of tumors by CT scan or MRI will be performed to assess the anti-tumor effect of zanu-cab tumour necrosis factor (TNF)-alpha inhibitors, anti-T cell antibodies (due to risk of immunosuppression).

[0470] Brain MRI or CT scan should be performed with the same frequency as the CT / MRI of the chest, abdomen, and pelvis and only if brain metastases are detected in the screening scan. Additional imaging of anatomical sites (e.g., head, neck) should be performed according to the patient's tumor type. Note that if there is a reason to assess bone lesions, these assessments will be performed as part of the CT or MRI assessments and do not require additional radiologic skeletal scan assessments.

[0471] Additional scans can be performed to appropriately confirm responses. The requirement for any confirmatory scans will generally be at the next scheduled assessment timepoint on the schedule or at a follow-up visit. A window of +3 days is allowed only for the first tumor assessment. Thereafter, a window of ±3 days is allowed, but should be performed prior to the start of the next treatment cycle. Patients who discontinue treatment for reasons other than disease progression and who have not withdrawn consent will be assessed for disease status every 8 weeks for up to 12 months or until disease progression and / or initiation of new anticancer therapy or withdrawal of consent, whichever occurs first.

[0472] A whole-body skeletal scan will be performed every 8 weeks for the first 12 months of treatment and every 12 weeks thereafter. Tumor assessments will be done according to the PCWG3-modified RECIST criteria.

[0473] Tumor markers

[0474] PSA levels will be assessed prior to the start of treatment and on Day 1 of each cycle (every 4 weeks ± 3 days). Repeat assessments should be performed using the same laboratory.

[0475] Tumor marker levels will be followed throughout the course of treatment.

[0476] Tumor tissue sample evaluation

[0477] PTEN analysis will be performed in baseline biopsies (preferably fresh; banked samples collected within 2 years are acceptable, provided that the biopsy was collected after castration resistance was established) by IHC (local or central) or next generation sequencing to identify patients with PTEN wild-type status.

[0478] Example 3

[0479] mCRPC patients with histologically confirmed prostate adenocarcinoma are enrolled following the clinical trial procedures of Example 2. After study entry, patients with progressive disease are treated with abiraterone acetate or enzalutamide, continue with their backbone AR-axis-targeting drug, and receive zanaburumumab combination therapy. Metastatic involvement sites include lymph nodes, bone, and / or internal organs. When sufficient biological material is available, the tumor PTEN status of patients is established by IHC using the Roche Ventana Optiview kit DAB and SP218 PTEN antibody using the Benchmark Ultra immunohistochemistry automated slide stainer. The OptiView DAB IHC Detection Kit (OptiView) is an indirect, biotin-free system for the detection of mouse IgG, mouse IgM, and rabbit primary antibodies. The kit is designed to identify targets in formalin-fixed, paraffin-embedded and frozen tissues by IHC, which are stained on the VENTANA automated slide stainer and observed by light microscopy. Any staining or absence of staining is supplemented by morphological studies and evaluation of appropriate controls for clinical interpretation.

[0480] No treatment-emergent adverse events (TEAEs) related to study treatment classified as grade 3 TEAEs or higher were observed in the cohort of 10 patients receiving treatment. In addition, the combination of zanaburumumab with abiraterone acetate or enzalutamide was well tolerated and no safety concerns were noted. Furthermore, no treatment was discontinued due to adverse events and no unexpected signals of toxicity were reported. Only one single IRR was reported (i.e., grade 2, related).

[0481] Example 4

[0482] A 77-year-old male with mCRPC was treated with the combination of zanohulimab and abiraterone acetate / prednisone according to the clinical trial protocol of Example 2. This patient had previously received four systemic treatments, including one chemotherapy and two androgen receptor axis-targeted drugs (i.e., darolutamide and abiraterone), but showed disease progression after these treatments. PTEN loss was observed by IHC testing on a pre-banked prostate biopsy sample. Blood-based next-generation sequencing testing did not detect tumor-related somatic alterations or mutations. According to the investigator report, the patient had developed lymph node progression (non-target) and bone tissue metastases prior to enrollment. During study treatment, the patient had the best overall response: RECIST disease stable (4 months) and PCWG3 bone scan disease stable (4 months), overall stable. After five months of continued treatment, there was no evidence of lymph node or bone progression reported, which is consistent with radiological disease control.

[0483] Example 5

[0484] A 77-year-old male with mCRPC was treated with the combination of zanohulimab and abiraterone acetate / prednisone according to the clinical trial protocol of Example 2. This patient had previously received four systemic treatments, including one chemotherapy and two androgen receptor axis-targeted drugs (i.e., darolutamide and abiraterone), but showed disease progression after these treatments. PTEN loss was observed by IHC testing on a pre-banked prostate biopsy sample. Blood-based next-generation sequencing testing did not detect tumor-related somatic alterations or mutations. According to the investigator report, the patient had developed lymph node progression (non-target) and bone tissue metastases prior to enrollment. During study treatment, the patient had the best overall response: RECIST disease stable (4 months) and PCWG3 bone scan disease stable (4 months), overall stable. After five months of continued treatment, there was no evidence of lymph node or bone progression reported, which is consistent with radiological disease control.

[0485] Example 6

[0486] A 77-year-old male with mCRPC was treated with the combination of zanohulimab and abiraterone acetate / prednisone according to the clinical trial protocol of Example 2. This patient had previously received four systemic treatments, including one chemotherapy and two androgen receptor axis-targeted drugs (i.e., darolutamide and abiraterone), but showed disease progression after these treatments. PTEN loss was observed by IHC testing on a pre-banked prostate biopsy sample. Blood-based next-generation sequencing testing did not detect tumor-related somatic alterations or mutations. According to the investigator report, the patient had developed lymph node progression (non-target) and bone tissue metastases prior to enrollment. During study treatment, the patient had the best overall response: RECIST disease stable (4 months) and PCWG3 bone scan disease stable (4 months), overall stable. After five months of continued treatment, there was no evidence of lymph node or bone progression reported, which is consistent with radiological disease control. androgen receptor axis-targeted drugs such as docetaxel, abiraterone (in combination with prednisone), and enzalutamide, but showed disease progression after these treatments. IHC testing of archived tumor samples from prior prostate biopsies showed that the patient's tumor was PTEN wild-type. Blood-based next generation sequencing testing detected only a missense mutation in TP53 (A161T) and a nonsense mutation in APC (K139*). Based on study treatment, the patient had best overall response of stable disease according to RECIST vl. l measurements of the patient's target lesion (lymph node) as reported by the investigator. The patient discontinued treatment with the occurrence of a skeletal-related event.

[0487] Example 7

[0488] Two additional patients were treated with the combination of zanlibutamab and enzalutamide according to the clinical trial protocol of Example 2, with PTEN status established using IHC testing as wild-type. PSA values will be evaluated for improvement trends at least 12 weeks after treatment initiation according to PCWG3 criteria. Imaging studies will be performed at pre-specified time points within the same timeframe to assess radiological disease control. These patients have previously received multiple systemic treatments, including chemotherapy and androgen receptor axis-targeted drugs such as abiraterone, docetaxel in combination with bicalutamide; cabazitaxel or prednisone in combination with enzalutamide, but showed disease progression after these treatments.

[0489] The following corresponds to the original claims in the parent application, which are now incorporated herein as part of the specification:

[0490] 1. A bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3 for use in a method of treating castration-resistant prostate cancer in an individual.

[0491] 2. A method of treating an individual having castration-resistant prostate cancer, the method comprising administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that can bind to an extracellular portion of ERBB2 and an antigen-binding site that can bind to an extracellular portion of ERBB3.

[0492] 3. The bispecific antibody for use or the method of claim 1 or 2, wherein the cancer has progressed after prior treatment with an androgen receptor axis-targeted agent.

[0493] 4. The bispecific antibody for use or method of any of clause 3, wherein the androgen receptor axis-targeting agent is an androgen receptor antagonist, such as a second-generation androgen receptor antagonist.

[0494] 5. The bispecific antibody for use or method of clause 4, wherein the androgen receptor antagonist is enzalutamide.

[0495] 6. The bispecific antibody for use or method of any of clause 3, wherein the androgen receptor axis-targeting agent is an androgen synthesis inhibitor, such as abiraterone acetate.

[0496] 7. The bispecific antibody for use or method of any of the preceding clauses, wherein the method of treatment further comprises use of an androgen receptor axis-targeting agent.

[0497] 8. The bispecific antibody for use or method of any of clauses 1 to 6, wherein the method of treatment further comprises use of an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, such as enzalutamide.

[0498] 9. The bispecific antibody for use or method of any of clauses 1 to 6, wherein the method of treatment further comprises use of an androgen synthesis inhibitor, such as abiraterone acetate.

[0499] 10. The bispecific antibody for use or method of any of clauses 1 to 4, wherein the cancer has progressed following prior treatment with an androgen receptor antagonist, and the method of treatment with the bispecific antibody further comprises use of an androgen receptor antagonist.

[0500] 11. The bispecific antibody for use or method of clause 10, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody are the same.

[0501] 12. The bispecific antibody for use or method of clause 10 or 11, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the method of treatment with the bispecific antibody are both enzalutamide.

[0502] 13. The bispecific antibody for use or method of clause 8 or 12, wherein the enzalutamide is administered at 160 mg once a day.

[0503] 14. The bispecific antibody for use or method of any one of clauses 1 to 3 or clause 6, wherein the cancer has progressed after prior treatment with an androgen synthesis inhibitor, and the method of treatment with the bispecific antibody further comprises use of an androgen synthesis inhibitor.

[0504] 15. The bispecific antibody for use or method of clause 14, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment with the bispecific antibody are the same.

[0505] 16. The bispecific antibody for use or method of clause 14 or 15, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the method of treatment with the bispecific antibody are both abiraterone acetate.

[0506] 17. The bispecific antibody for use or method of clause 9 or 16, wherein the abiraterone acetate is administered at 1000 mg once per day.

[0507] 18. The bispecific antibody for use or method of clause 17, wherein the abiraterone acetate is administered in combination with 5 mg prednisone twice per day.

[0508] 19. The bispecific antibody for use or method of any of the preceding clauses, wherein the method of treatment comprises administration of the bispecific antibody at a quantity of 750 mg once every two weeks.

[0509] 20. The bispecific antibody for use or method of any of the preceding clauses, wherein the cancer is not NRG1 fusion positive.

[0510] 21. The bispecific antibody for use or method of clause 7, wherein the androgen receptor axis-targeting agent is administered according to a medical prescription as indicated by a health authority such as the FDA.

[0511] 22. The bispecific antibody for use or method of any of the preceding clauses, wherein the cancer is characterized as a prostate adenocarcinoma that does not have histologically confirmed neuroendocrine differentiation or small cell features.

[0512] 23. The bispecific antibody for use or method of any of the preceding clauses, wherein the bispecific antibody comprises a first antigen binding site that can bind domain I of ERBB2, and a second antigen binding site that can bind domain III of ERBB3.

[0513] 24. The bispecific antibody for use or method of any of the preceding items, wherein the bispecific antibody comprises

[0514] i) at least CDR1, CDR2 and CDR3 sequences in an ERBB2-specific heavy chain variable region selected from the group consisting of MF2973, MF3004,

[0515] MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 and MF3003, or wherein the antibody comprises CDR sequences that differ from those of MF2973, MF3004,

[0516] MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 or MF3003 by at most 3 amino acids, preferably at most 2 amino acids, preferably at most 1 amino acid; and / or ii) at least CDR1, CDR2 and CDR3 sequences in an ERBB3-specific heavy chain variable region selected from the group consisting of MF3178; MF3176;

[0517] MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060;

[0518] MF6061 ; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067;

[0519] MF6068; MF6069; MF6070; MF6071 ; MF6072; MF6073 and MF6074, or wherein the antibody comprises CDR sequences that differ from those of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058;

[0520] MF6059; MF6060; MF6061 ; MF6062; MF6063; MF6064; MF6065;

[0521] MF6066; MF6067; MF6068; MF6069; MF6070; MF6071 ; MF6072;

[0522] MF6059; MF6060; MF6061 ; MF6062; MF6063; MF6064; MF6065;

[0523] MF6066; MF6067; MF6068; MF6069; MF6070; MF6071 ; MF6072;MF6073 or MF6074.

[0524] 25. The bispecific antibody for use or method of any of the preceding items, wherein the bispecific antibody comprises

[0525] i) an ERBB2-specific heavy chain variable region sequence selected from the group consisting of heavy chain variable region sequences of MF2973, MF3004, MF3958, MF2971, MF3025, MF2916,

[0526] MF3991, MF3031, and MF3003, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of MF2973, MF3004,

[0527] MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, or MF3003 by up to 15 amino acids;

[0528] and / or

[0529] ii) an ERBB3-specific heavy chain variable region sequence selected from the group consisting of heavy chain variable region sequences of MF3178; MF3176; MF3163; MF6055; MF6056; MF6057;

[0530] MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064;

[0531] MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071;

[0532] MF6072; MF6073, and MF6074, or wherein the antibody comprises a heavy chain variable region sequence that differs from the heavy chain variable region sequence of MF3178; MF3176;

[0533] MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060;

[0534] MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067;

[0535] MF6068; MF6069; MF6070; MF6071; MF6072; MF6073, or MF6074.

[0536] 26. The bispecific antibody for use or method of any of the preceding clauses, wherein the bispecific antibody comprises the heavy chain variable region sequences of MF3958 and MF3178.

[0537] 27. The bispecific antibody for use or method of any of the preceding clauses, wherein the bispecific antibody comprises a variable domain comprising the first antigen binding site and a variable domain comprising the second antigen binding site, and wherein the first and second antigen binding sites comprise a light chain variable region comprising a CDR1 comprising the sequence QSISSY, a CDR2 comprising the sequence AAS, and a CDR3 comprising the sequence QQSYSTPPT.

[0538] 28. The bispecific antibody for use or method of any of the preceding clauses, wherein the individual is a human individual.

[0539] 29. The bispecific antibody for use or method of any of the preceding clauses, wherein the cancer is metastatic castration-resistant prostate cancer, or wherein the individual is at risk of developing metastatic castration-resistant prostate cancer.

[0540] 30. A kit-of-parts comprising a bispecific antibody comprising an antigen binding site that can bind an extracellular part of ERBB2 and an antigen binding site that can bind an extracellular part of ERBB3 and an androgen receptor axis-targeting agent.

[0541] 31. The kit-of-parts of clause 30, further comprising instructions for use.

[0542] 32. The kit-of-parts of clause 30 or 31, wherein the instructions for use comprise instructions for administration of the bispecific antibody and the androgen receptor axis-targeting agent.

[0543] 33. The kit-of-parts of any of clauses 30 to 32, wherein the androgen receptor axis-targeting agent comprises an androgen receptor antagonist such as a second-generation androgen receptor antagonist such as enzalutamide, or an androgen synthesis inhibitor such as abiraterone acetate, and wherein the bispecific antibody comprises zenocutuzumab.

[0544] 34. The kit-of-parts of clause 33, wherein the instructions for use comprise administration of 1000 mg abiraterone acetate once a day in combination with 5 mg prednisone twice a day, and administration of the bispecific antibody in an amount of 750 mg once every two weeks.

[0545] 35. The kit-of-parts of clause 33, wherein the instructions for use comprise administration of 160 mg enzalutamide once a day and administration of the bispecific antibody in an amount of 750 mg once every two weeks.

[0546] 36. The kit-of-parts of clause 34 or 35, wherein the instructions for use of the abiraterone acetate or enzalutamide comprise instructions for oral administration, and the administration of the bispecific antibody comprises instructions for intravenous injection.

Claims

1. A bispecific antibody comprising an antigen-binding site that binds to the extracellular portion of ERBB2 and an antigen-binding site that binds to the extracellular portion of ERBB3, for use in a method of treating an individual with castration-resistant prostate cancer.

2. A method for treating an individual with castration-resistant prostate cancer, the method comprising administering to the individual a therapeutically effective amount of a bispecific antibody comprising an antigen-binding site that binds to the extracellular portion of ERBB2 and an antigen-binding site that binds to the extracellular portion of ERBB3.

3. The bispecific antibody or method for use as described in claim 1 or 2, wherein the cancer has worsened after prior treatment with an androgen receptor axis-targeting agent.

4. The bispecific antibody or method for use as described in claim 3, wherein the androgen receptor axis-targeting agent is an androgen receptor antagonist, such as a second-generation androgen receptor antagonist.

5. The bispecific antibody or method for use as described in claim 4, wherein the androgen receptor antagonist is enzalutamide.

6. The bispecific antibody or method for use as described in claim 3, wherein the androgen receptor axis-targeting agent is an androgen synthesis inhibitor, such as abiraterone acetate.

7. The bispecific antibody or method for use as described in any of the preceding claims, wherein the treatment method further comprises the use of an androgen receptor axis-targeting agent.

8. The bispecific antibody or method for use as described in any one of claims 1 to 6, wherein the treatment method further comprises the use of an androgen receptor antagonist, such as a second-generation androgen receptor antagonist, such as enzalutamide.

9. The bispecific antibody or method for use as described in any one of claims 1 to 6, wherein the treatment method further comprises the use of an androgen synthesis inhibitor, such as abiraterone acetate.

10. The bispecific antibody or method for use as claimed in any one of claims 1 to 4, wherein the cancer has worsened after prior treatment with an androgen receptor antagonist, and the treatment method using the bispecific antibody further comprises the use of an androgen receptor antagonist.

11. The bispecific antibody or method for use as described in claim 10, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the treatment method using the bispecific antibody are the same.

12. The bispecific antibody or method for use as described in claim 10 or 11, wherein the androgen receptor antagonist used in the prior treatment and the androgen receptor antagonist further used in the treatment method using the bispecific antibody are both enzalutamide.

13. The bispecific antibody or method for use as described in claim 8 or 12, wherein enzalutamide is administered at 160 mg once daily.

14. The bispecific antibody or method for use as claimed in any one of claims 1 to 3 or 6, wherein the cancer has worsened after prior treatment with an androgen synthesis inhibitor, and the treatment method using the bispecific antibody further comprises the use of an androgen synthesis inhibitor.

15. The bispecific antibody or method for use as described in claim 14, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the treatment method using the bispecific antibody are the same.

16. The bispecific antibody or method for use as described in claim 14 or 15, wherein the androgen synthesis inhibitor used in the prior treatment and the androgen synthesis inhibitor further used in the treatment method using the bispecific antibody are both abiraterone acetate.

17. The bispecific antibody or method for use as described in claim 9 or 16, wherein abiraterone acetate is administered at 1000 mg once daily.

18. The bispecific antibody or method for use as described in claim 17, wherein abiraterone acetate is administered in combination with 5 mg prednisone twice daily.

19. The bispecific antibody or method for use as described in any of the preceding claims, wherein the treatment comprises administering a dose of 750 mg of the bispecific antibody every two weeks.

20. The bispecific antibody or method for use as described in any of the preceding claims, wherein the cancer is not NRG1 fusion positive.

21. The bispecific antibody or method for use as described in claim 7, wherein the androgen receptor axis-targeting agent is administered according to medical prescribing instructions issued by a health authority such as the FDA.

22. The bispecific antibody or method for use as described in any of the preceding claims, wherein the cancer is histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small cell characteristics.

23. The bispecific antibody or method for use as described in any of the preceding claims, wherein the bispecific antibody comprises a first antigen-binding site capable of binding domain I of ERBB2 and a second antigen-binding site capable of binding domain III of ERBB3.

24. A bispecific antibody or method for use as described in any of the preceding claims, wherein the bispecific antibody comprises i) At least CDR1, CDR2, and CDR3 sequences in the ERBB2-specific heavy chain variable region, wherein the ERBB2-specific heavy chain variable region is selected from the group consisting of: MF2973, MF3004. MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 and MF3003, Or the antibody may contain a CDR sequence that differs from the following CDR1, CDR2, and CDR3 sequences by a maximum of 3 amino acids, preferably a maximum of 2 amino acids, and preferably a maximum of 1 amino acid: MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 or MF3003; and / or ii) At least CDR1, CDR2 and CDR3 sequences in the ERBB3-specific heavy chain variable region, which is selected from the group consisting of: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, Or the antibody may contain a CDR sequence that differs from the following CDR1, CDR2, and CDR3 sequences by a maximum of 3 amino acids, preferably a maximum of 2 amino acids, and preferably a maximum of 1 amino acid: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074.

25. A bispecific antibody or method for use as described in any of the preceding claims, wherein the bispecific antibody comprises i) ERBB2-specific heavy chain variable region sequences selected from the group consisting of the following heavy chain variable region sequences: MF2973, MF3004, MF3958, MF2971, MF3025, MF2916. MF3991, MF3031, and MF3003, or said antibodies comprising a heavy chain variable region sequence that differs from the following heavy chain variable region sequences by up to 15 amino acids: MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 or MF3003; and / or ii) ERBB3-specific heavy chain variable region sequences selected from the group consisting of the following heavy chain variable region sequences: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 and MF6074, or said antibody comprising a heavy chain variable region sequence that differs from the following heavy chain variable region sequences by up to 15 amino acids: MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF 6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 or MF6074.

26. The bispecific antibody or method for use as described in any of the preceding claims, wherein the bispecific antibody comprises the heavy chain variable region sequences of MF3958 and MF3178.

27. The bispecific antibody or method for use as claimed in any one of the claims, wherein the bispecific antibody comprises a variable domain containing the first antigen binding site and a variable domain containing the second antigen binding site, and wherein the first and second antigen binding sites comprise a light chain variable region comprising a CDR1 containing the sequence QSISSY, a CDR2 containing the sequence AAS, and a CDR3 containing the sequence QQSYSTPPT.

28. The bispecific antibody or method for use as described in any of the preceding claims, wherein the individual is a human individual.

29. The bispecific antibody or method for use as described in any of the preceding claims, wherein the cancer is metastatic castration-resistant prostate cancer, or wherein the individual is at risk of developing metastatic castration-resistant prostate cancer.

30. A multi-component kit comprising a bispecific antibody and an androgen receptor axis-targeting agent, wherein the bispecific antibody comprises an antigen-binding site that binds to the extracellular portion of ERBB2 and an antigen-binding site that binds to the extracellular portion of ERBB3.

31. The multi-component kit of claim 30, further comprising an instruction manual.

32. The multi-component kit of claim 30 or 31, wherein the instructions for use include instructions for administering the bispecific antibody and the androgen receptor axis-targeting agent.

33. The multi-component kit of any one of claims 30 to 32, wherein the androgen receptor axis-targeting agent comprises an androgen receptor antagonist such as a second-generation androgen receptor antagonist such as enzalutamide, or comprises an androgen synthesis inhibitor such as abiraterone acetate, and wherein the bispecific antibody comprises zenocutuzumab.

34. The multi-component kit of claim 33, wherein the instructions for use include administration of a combination of 1000 mg abiraterone acetate once daily and 5 mg prednisone twice daily, and administration of 750 mg of bispecific antibody once every two weeks.

35. The multi-component kit of claim 33, wherein the instructions for use include administration of 160 mg enzalutamide once daily and 750 mg of bispecific antibody once every two weeks.

36. The multi-component kit of claim 34 or 35, wherein the instructions for use of the abiraterone acetate or enzalutamide include instructions for oral administration, and the instructions for administration of the bispecific antibody include instructions for intravenous injection.

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