Bispecific antigen-binding molecules that bind a staphylococcus target antigen and a complement component and uses thereof

Abstract

According to certain embodiments, the present disclosure provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds a Staphylococcus species target antigen and a second antigen binding domain that binds a complement component. In certain embodiments, the bispecific antigen-binding molecules of the present disclosure are capable of binding to the Staphylococcus species target antigen with an EC50, of about 10 nM or less, and/or are capable of promoting complement deposition on the Staphylococcus species with an EC50, of about 10 nM. The antibodies of the disclosure are useful for treating diseases in which inhibition or reduction of the growth of a Staphylococcus species is desired and/or therapeutically beneficial, for example, for treating staphylococcal infections including a skin infection, cellulitis, pneumonia, meningitis, urinary tract infection, toxic shock syndrome, endocarditis, osteomyelitis, bacteremia, or sepsis, or for preventing or treating a Staphylococcus infection that occurs as a result of a surgical procedure.

What is claimed is: 
     
         1 . An isolated bispecific antigen-binding molecule comprising:
 a) a first antigen-binding domain that binds a  Staphylococcus  species target antigen; and   b) a second antigen-binding domain that binds a complement component.   
     
     
         2 .- 10 . (canceled) 
     
     
         11 . The isolated bispecific antigen binding molecule of  claim 1 , wherein the first antigen-binding domain comprises:
 three heavy chain complementarity determining regions (HCDRs) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 154; and   three light chain complementarity determining regions (LCDRs) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO: 162.   
     
     
         12 .- 18 . (canceled) 
     
     
         19 . The isolated bispecific antigen binding molecule of  claim 1 , wherein the second antigen-binding domain comprises three HCDRs contained with an HCVR comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:10, SEQ ID NO:18, SEQ ID NO:26, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:50, SEQ ID NO:58, SEQ ID NO:66, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:90, SEQ ID NO:98, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:122, or SEQ ID NO:130, and three LCDRs contained with an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162. 
     
     
         20 .- 48 . (canceled) 
     
     
         49 . A nucleic acid comprising a nucleotide sequence that encodes a bispecific antigen-binding molecule, wherein the bispecific antigen-binding molecule comprises:
 (a) a first antigen antigen-binding domain that binds a  Staphylococcus  species target antigen, wherein the first antigen-binding domain comprises three HCDRs contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 154, and three LCDRs contained within an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162; and   (b) a second antigen-binding domain that binds a complement component, wherein the second antigen-binding domain comprises three HCDRs contained with an HCVR comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:10, SEQ ID NO:18, SEQ ID NO:26, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:50, SEQ ID NO:58, SEQ ID NO:66, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:90, SEQ ID NO:98, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:122, or SEQ ID NO:130, and three LCDRs contained with an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162.   
     
     
         50 . The nucleic acid of  claim 49 , wherein the first antigen-binding domain comprises:
 an HCVR comprising the amino acid sequence of SEQ ID NO:138 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:154 and an LCVR comprising the amino acid sequence of SEQ ID NO:162.   
     
     
         51 . The nucleic acid of  claim 49 , wherein the second antigen-binding domain comprises:
 an HCVR comprising the amino acid sequence of SEQ ID NO:2 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:10 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:90 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:98 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:106 and an LCVR comprising the amino acid sequence of SEQ ID NO:146; or   an HCVR comprising the amino acid sequence of SEQ ID NO:66 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:74 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:82 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:18 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:26 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:34 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:42 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:50 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:58 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:114 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:122 and an LCVR comprising the amino acid sequence of SEQ ID NO:162; or   an HCVR comprising the amino acid sequence of SEQ ID NO:130 and an LCVR comprising the amino acid sequence of SEQ ID NO:162.   
     
     
         52 . An expression vector comprising the nucleic acid of  claim 49 . 
     
     
         53 . A host cell comprising the expression vector of  claim 52 . 
     
     
         54 . A method of inhibiting the growth of a  Staphylococcus  species in a subject, the method comprising administering to the subject a bispecific antigen-binding molecule comprising a first antigen antigen-binding domain that binds a  Staphylococcus  species target antigen and a second antigen-binding domain that binds a complement component. 
     
     
         55 . The method of  claim 54 , wherein the  Staphylococcus  species is  Staphylococcus aureus.    
     
     
         56 . The method of  claim 54 , wherein the  Staphylococcus  species is a methicillin resistant  Staphylococcus aureus.    
     
     
         57 . The method of  claim 54 , wherein the first antigen-binding domain binds iron regulated surface determinant B (IsdB) and the second antigen-binding domain binds complement component C1q. 
     
     
         58 . The method of  claim 57 , wherein the first antigen-binding domain comprises three HCDRs contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 154 and three LCDRs contained within an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162. 
     
     
         59 . The method of  claim 58 , wherein the first antigen-binding domain comprises:
 an HCDR1 comprising the amino acid sequence of SEQ ID NO:140, an HCDR2 comprising the amino acid sequence of SEQ ID NO:142, an HCDR3 comprising the amino acid sequence of SEQ ID NO:144, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:156, an HCDR2 comprising the amino acid sequence of SEQ ID NO:158, an HCDR3 comprising the amino acid sequence of SEQ ID NO:160, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168.   
     
     
         60 . The method of  claim 57 , wherein the second antigen-binding domain comprises three HCDRs contained with an HCVR comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:10, SEQ ID NO:18, SEQ ID NO:26, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:50, SEQ ID NO:58, SEQ ID NO:66, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:90, SEQ ID NO:98, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:122, or SEQ ID NO:130, and three LCDRs contained with an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162. 
     
     
         61 . The method of  claim 60 , wherein the second antigen-binding domain comprises:
 an HCDR1 comprising the amino acid sequence of SEQ ID NO:4, an HCDR2 comprising the amino acid sequence of SEQ ID NO:6, an HCDR3 comprising the amino acid sequence of SEQ ID NO:8, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:12, an HCDR2 comprising the amino acid sequence of SEQ ID NO:14, an HCDR3 comprising the amino acid sequence of SEQ ID NO:16, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:92, an HCDR2 comprising the amino acid sequence of SEQ ID NO:94, an HCDR3 comprising the amino acid sequence of SEQ ID NO:96, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:100, an HCDR2 comprising the amino acid sequence of SEQ ID NO:102, an HCDR3 comprising the amino acid sequence of SEQ ID NO:104, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:108, an HCDR2 comprising the amino acid sequence of SEQ ID NO:110, an HCDR3 comprising the amino acid sequence of SEQ ID NO:112, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:68, an HCDR2 comprising the amino acid sequence of SEQ ID NO:70, an HCDR3 comprising the amino acid sequence of SEQ ID NO:72, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:76, an HCDR2 comprising the amino acid sequence of SEQ ID NO:78, an HCDR3 comprising the amino acid sequence of SEQ ID NO:80, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:84, an HCDR2 comprising the amino acid sequence of SEQ ID NO:86, an HCDR3 comprising the amino acid sequence of SEQ ID NO:88, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:20, an HCDR2 comprising the amino acid sequence of SEQ ID NO:22, an HCDR3 comprising the amino acid sequence of SEQ ID NO:24, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:28, an HCDR2 comprising the amino acid sequence of SEQ ID NO:30, an HCDR3 comprising the amino acid sequence of SEQ ID NO:32, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:36, an HCDR2 comprising the amino acid sequence of SEQ ID NO:38, an HCDR3 comprising the amino acid sequence of SEQ ID NO:40, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:44, an HCDR2 comprising the amino acid sequence of SEQ ID NO:46, an HCDR3 comprising the amino acid sequence of SEQ ID NO:48, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:52, an HCDR2 comprising the amino acid sequence of SEQ ID NO:54, an HCDR3 comprising the amino acid sequence of SEQ ID NO:56, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:60, an HCDR2 comprising the amino acid sequence of SEQ ID NO:62, an HCDR3 comprising the amino acid sequence of SEQ ID NO:64, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:116, an HCDR2 comprising the amino acid sequence of SEQ ID NO:118, an HCDR3 comprising the amino acid sequence of SEQ ID NO:120, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:124, an HCDR2 comprising the amino acid sequence of SEQ ID NO:126, an HCDR3 comprising the amino acid sequence of SEQ ID NO:128, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:132, an HCDR2 comprising the amino acid sequence of SEQ ID NO:134, an HCDR3 comprising the amino acid sequence of SEQ ID NO:136, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168.   
     
     
         62 . The method of  claim 54 , wherein the bispecific antigen-binding molecule comprises:
 a first antigen-binding domain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:140, an HCDR2 comprising the amino acid sequence of SEQ ID NO:142, an HCDR3 comprising the amino acid sequence of SEQ ID NO:144, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; and   a second antigen-binding domain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:4, an HCDR2 comprising the amino acid sequence of SEQ ID NO:6, an HCDR3 comprising the amino acid sequence of SEQ ID NO:8, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152.   
     
     
         63 . The method of  claim 54 , wherein the subject has a disease or disorder comprising a skin infection, cellulitis, pneumonia, meningitis, urinary tract infection, toxic shock syndrome, endocarditis, pericarditis, osteomyelitis, bacteremia, or sepsis. 
     
     
         64 . The method of  claim 54 , wherein the subject has undergone or will be undergoing a surgical procedure. 
     
     
         65 . A method of treating a disease or disorder caused by a  Staphylococcus  species, the method comprising administering to a subject having the disease or disorder a bispecific antigen-binding molecule comprising a first antigen antigen-binding domain that binds a  Staphylococcus  species target antigen and a second antigen-binding domain that binds a complement component. 
     
     
         66 . The method of  claim 65 , wherein the  Staphylococcus  species is  Staphylococcus aureus.    
     
     
         67 . The method of  claim 65 , wherein the  Staphylococcus  species is a methicillin resistant  Staphylococcus aureus.    
     
     
         68 . The method of  claim 65 , wherein the disease or disorder is a skin infection, cellulitis, pneumonia, meningitis, urinary tract infection, toxic shock syndrome, endocarditis, pericarditis, osteomyelitis, bacteremia, or sepsis. 
     
     
         69 . The method of  claim 65 , wherein the first antigen-binding domain binds iron regulated surface determinant B (IsdB) and the second antigen-binding domain binds complement component C1q. 
     
     
         70 . The method of  claim 69 , wherein the first antigen-binding domain comprises three HCDRs contained within an HCVR comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 154 and three LCDRs contained within an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162. 
     
     
         71 . The method of  claim 70 , wherein the first antigen-binding domain comprises:
 an HCDR1 comprising the amino acid sequence of SEQ ID NO:140, an HCDR2 comprising the amino acid sequence of SEQ ID NO:142, an HCDR3 comprising the amino acid sequence of SEQ ID NO:144, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:156, an HCDR2 comprising the amino acid sequence of SEQ ID NO:158, an HCDR3 comprising the amino acid sequence of SEQ ID NO:160, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168.   
     
     
         72 . The method of  claim 69 , wherein the second antigen-binding domain comprises three HCDRs contained with an HCVR comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:10, SEQ ID NO:18, SEQ ID NO:26, SEQ ID NO:34, SEQ ID NO:42, SEQ ID NO:50, SEQ ID NO:58, SEQ ID NO:66, SEQ ID NO:74, SEQ ID NO:82, SEQ ID NO:90, SEQ ID NO:98, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:122, or SEQ ID NO:130, and three LCDRs contained with an LCVR comprising the amino acid sequence of SEQ ID NO:146 or SEQ ID NO:162. 
     
     
         73 . The method of  claim 72 , wherein the second antigen-binding domain comprises:
 an HCDR1 comprising the amino acid sequence of SEQ ID NO:4, an HCDR2 comprising the amino acid sequence of SEQ ID NO:6, an HCDR3 comprising the amino acid sequence of SEQ ID NO:8, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:12, an HCDR2 comprising the amino acid sequence of SEQ ID NO:14, an HCDR3 comprising the amino acid sequence of SEQ ID NO:16, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:92, an HCDR2 comprising the amino acid sequence of SEQ ID NO:94, an HCDR3 comprising the amino acid sequence of SEQ ID NO:96, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:100, an HCDR2 comprising the amino acid sequence of SEQ ID NO:102, an HCDR3 comprising the amino acid sequence of SEQ ID NO:104, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:108, an HCDR2 comprising the amino acid sequence of SEQ ID NO:110, an HCDR3 comprising the amino acid sequence of SEQ ID NO:112, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:68, an HCDR2 comprising the amino acid sequence of SEQ ID NO:70, an HCDR3 comprising the amino acid sequence of SEQ ID NO:72, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:76, an HCDR2 comprising the amino acid sequence of SEQ ID NO:78, an HCDR3 comprising the amino acid sequence of SEQ ID NO:80, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:84, an HCDR2 comprising the amino acid sequence of SEQ ID NO:86, an HCDR3 comprising the amino acid sequence of SEQ ID NO:88, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:20, an HCDR2 comprising the amino acid sequence of SEQ ID NO:22, an HCDR3 comprising the amino acid sequence of SEQ ID NO:24, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:28, an HCDR2 comprising the amino acid sequence of SEQ ID NO:30, an HCDR3 comprising the amino acid sequence of SEQ ID NO:32, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:36, an HCDR2 comprising the amino acid sequence of SEQ ID NO:38, an HCDR3 comprising the amino acid sequence of SEQ ID NO:40, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:44, an HCDR2 comprising the amino acid sequence of SEQ ID NO:46, an HCDR3 comprising the amino acid sequence of SEQ ID NO:48, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:52, an HCDR2 comprising the amino acid sequence of SEQ ID NO:54, an HCDR3 comprising the amino acid sequence of SEQ ID NO:56, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:60, an HCDR2 comprising the amino acid sequence of SEQ ID NO:62, an HCDR3 comprising the amino acid sequence of SEQ ID NO:64, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:116, an HCDR2 comprising the amino acid sequence of SEQ ID NO:118, an HCDR3 comprising the amino acid sequence of SEQ ID NO:120, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:124, an HCDR2 comprising the amino acid sequence of SEQ ID NO:126, an HCDR3 comprising the amino acid sequence of SEQ ID NO:128, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168; or   an HCDR1 comprising the amino acid sequence of SEQ ID NO:132, an HCDR2 comprising the amino acid sequence of SEQ ID NO:134, an HCDR3 comprising the amino acid sequence of SEQ ID NO:136, an LCDR1 comprising the amino acid sequence of SEQ ID NO:164, an LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:168.   
     
     
         74 . The method of  claim 65 , wherein the bispecific antigen-binding molecule comprises:
 a first antigen-binding domain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:140, an HCDR2 comprising the amino acid sequence of SEQ ID NO:142, an HCDR3 comprising the amino acid sequence of SEQ ID NO:144, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152; and   a second antigen-binding domain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:4, an HCDR2 comprising the amino acid sequence of SEQ ID NO:6, an HCDR3 comprising the amino acid sequence of SEQ ID NO:8, an LCDR1 comprising the amino acid sequence of SEQ ID NO:148, an LCDR2 comprising the amino acid sequence of SEQ ID NO:150, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:152.