Antibody that binds erbb-2 and erbb-3

Abstract

The invention relates among others to antibodies comprising a first antigen-binding site that binds Erb B-2 and a second antigen-binding site that binds Erb B-3. The antibodies can typically reduce a ligand-induced receptor function of Erb B-3 on a Erb B-2 and Erb B-3 positive cell. Also described are method for the treatment and use of the antibodies in imaging and in the treatment of subjects having an Erb B-2, Erb B-3 or Erb B-2/3 positive tumor.

1 - 35 . (canceled) 
     
     
         36 . A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject an antibody comprising:
 a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein the antibody can reduce a ligand-induced receptor function of ErbB-3 on a ErbB-2 and ErbB-3 positive cell;   a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein said first antigen-binding site binds domain I of ErbB-2 and said second antigen-binding site binds domain III of ErbB-3;   a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, wherein the affinity (KD) of said second antigen-binding site for an ErbB-3 positive cell is equal to, or higher than, the affinity of said first antigen-binding site for an ErbB-2 positive cell;   two antigen-binding sites that bind ErbB-2, wherein at least one of said antigen-binding sites binds domain I of ErbB-2; or   two antigen-binding sites that bind ErbB-3, wherein at least one of said antigen-binding sites binds domain III of ErbB-3.   
     
     
         37 - 39 . (canceled) 
     
     
         40 . A method for the treatment of a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor or at risk of having said tumor comprising administering to the subject:
 a bispecific antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3, and   one or more compounds selected from the group consisting of an inhibitor of a component of the PI3Kinase pathway, an inhibitor of a component of the MAPK pathway, a microtubuli disrupting drug and an HDAC inhibitor, preferably one or more compounds selected from the group consisting of a tyrosine kinase inhibitor, a PI3Ka inhibitor, an Akt inhibitor, an mTOR inhibitor, an Src inhibitor, vorinostat and paclitaxel.   
     
     
         41 - 48 . (canceled) 
     
     
         49 . A method for counteracting the formation of a metastasis in a subject having a ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor, wherein said ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive tumor cell has a heregulin expression level that is at least 60%, preferably at least 70%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90% or 95% of the heregulin expression level of BXPC3 or MCF7 cells, comprising administering to the subject a bispecific antibody comprising a first antigen-binding site that binds ErbB-2 and a second antigen-binding site that binds ErbB-3. 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 36 , wherein said subject has an ErbB-2 or ErbB-2/ErbB-3 positive tumor that has less than 1.000.000 ErbB-2 cell-surface receptors per cell. 
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 36 , wherein said tumor is a breast cancer, gastric cancer, colorectal cancer, colon cancer, gastro-esophageal cancer, esophageal cancer, endometrial cancer, ovarian cancer, liver cancer, lung cancer including non-small cell lung cancer, clear cell sarcoma, salivary gland cancer, head and neck cancer, brain cancer, bladder cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, or melanoma tumor. 
     
     
         54 . The method of  claim 36 , wherein said subject has a cardiac function that is lower than 90% as compared to a healthy cardiac function. 
     
     
         55 . The method of  claim 54 , wherein said cardiac function comprises the Left Ventricular Ejection Fraction (LVEF). 
     
     
         56 . The method or antibody for use according to claim  39  or  54 - 55 , wherein said subject suffers from congestive heart failure (CHF), left ventricular dysfunction (LVD) and/or a≥10% decreased Left Ventricular Ejection Fraction (LVEF), and/or wherein said subject has had a myocardial infarction. 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 36 , wherein the antibody is a bispecific antibody comprising a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences of AYYIN (SEQ ID NO:49), RIYPGSGYTSYAQKFQG (SEQ ID NO:50), and PPVYYDSAWFAY (SEQ ID NO:51) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences GYYMH (SEQ ID NO:64), WINPNSGGTNYAQKFQG (SEQ ID NO:65), and DHGSRHFWSYWGFDY (SEQ ID NO:66) and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87. 
     
     
         59 . The method of  claim 36 , wherein the antibody is fucosylated in order to enhance antibody dependent cellular cytotoxicity (ADCC). 
     
     
         60 . The method of  claim 36 , wherein the antibody comprises two different immunoglobulin heavy chains with compatible heterodimerization domains. 
     
     
         61 . The method of  claim 60 , wherein the compatible heterodimerization domains are compatible immunoglobulin heavy chain CH3 heterodimerization domains. 
     
     
         62 . The method of  claim 36 , comprising administering to the subject at least one additional therapeutic agent. 
     
     
         63 . The method of  claim 62 , wherein said at least one additional therapeutic agent is selected from afatinib, laptinib, neratinib, BYL719, MK-2206, everolimus, saracatinib, paclitaxel, vorinostat. 
     
     
         64 . The method of  claim 36 , wherein the antibody comprises the light chain variable region comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 87). 
     
     
         65 . The method of  claim 36 , wherein the antibody comprises a first binding arm comprising a heavy chain variable region comprising SEQ ID NO: 48, a second binding arm comprising a heavy chain variable region comprising SEQ ID NO: 63, and both the first and second binding arms comprise a light chain variable region comprising SEQ ID NO: 87. 
     
     
         66 . The method of  claim 36 , wherein the antibody comprises a first binding arm comprising a heavy chain comprising SEQ ID NO: 88, a second binding arm comprising a heavy chain comprising SEQ ID NO: 89, and both the first and second binding arms comprise a light chain comprising SEQ ID NO: 87. 
     
     
         67 . The method of  claim 36 , wherein the tumor is a ErbB-2/ErbB-3 positive tumor. 
     
     
         68 . The method of  claim 36 , wherein the tumor is a ErbB-2 positive tumor. 
     
     
         69 . The method of  claim 36 , wherein the tumor is a ErbB-3 positive tumor. 
     
     
         70 . The method of  claim 36 , wherein the antibody is a bispecific antibody comprising:
 a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising:
 the CDR1 sequence of SEQ ID NO:24 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:24, the CDR2 sequence of SEQ ID NO:25 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:25, and the CDR3 sequence of SEQ ID NO:26 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:26, 
 the CDR1 sequence of SEQ ID NO:29 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:29, the CDR2 sequence of SEQ ID NO:30 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:30, and the CDR3 sequence of SEQ ID NO:31 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:31, 
 the CDR1 sequence of SEQ ID NO:34 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:34, the CDR2 sequence of SEQ ID NO:35 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:35, and the CDR3 sequence of SEQ ID NO:36 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:36, 
 the CDR1 sequence of SEQ ID NO:39 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:39, the CDR2 sequence of SEQ ID NO:40 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:40, and the CDR3 sequence of SEQ ID NO:41 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:41, 
 the CDR1 sequence of SEQ ID NO:54 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:54, the CDR2 sequence of SEQ ID NO:55 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:55, and the CDR3 sequence of SEQ ID NO:56 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:56, 
 the CDR1 sequence of SEQ ID NO:117 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:117, the CDR2 sequence of SEQ ID NO:118 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:118, and the CDR3 sequence of SEQ ID NO:119 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:119, or 
 the CDR1 sequence of SEQ ID NO:44 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:44, the CDR2 sequence of SEQ ID NO:45 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:45, and the CDR3 sequence of SEQ ID NO:46 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:46, and 
 a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87 or comprising CDR1, CDR2, and CDR3 sequences each having at most two conservative amino acid substitutions relative to the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87; and 
   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising:
 the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66, 
 the CDR1 sequence of SEQ ID NO:69 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:69, the CDR2 sequence of SEQ ID NO:70 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:70, and the CDR3 sequence of SEQ ID NO:71 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:71, 
 the CDR1 sequence of SEQ ID NO:74 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:74, the CDR2 sequence of SEQ ID NO:75 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:75, and the CDR3 sequence of SEQ ID NO:76 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:76, or 
 the CDR1 sequence of SEQ ID NO:79 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:79, the CDR2 sequence of SEQ ID NO:80 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:80, and the CDR3 sequence of SEQ ID NO:81 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:81, and 
 a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87 or comprising CDR1, CDR2, and CDR3 sequences each having at most two conservative amino acid substitutions relative to the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87. 
   
     
     
         71 . The method of  claim 36 , wherein the antibody is a bispecific antibody comprising:
 a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:24 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:24, the CDR2 sequence of SEQ ID NO:25 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:25, and the CDR3 sequence of SEQ ID NO:26 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:26, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:29 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:29, the CDR2 sequence of SEQ ID NO:30 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:30, and the CDR3 sequence of SEQ ID NO:31 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:31, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:34 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:34, the CDR2 sequence of SEQ ID NO:35 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:35, and the CDR3 sequence of SEQ ID NO:36 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:36, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:39 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:39, the CDR2 sequence of SEQ ID NO:40 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:40, and the CDR3 sequence of SEQ ID NO:41 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:41, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:44 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:44, the CDR2 sequence of SEQ ID NO:45 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:45, and the CDR3 sequence of SEQ ID NO:46 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:46, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:34 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:34, the CDR2 sequence of SEQ ID NO:35 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:35, and the CDR3 sequence of SEQ ID NO:36 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:36, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:69 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:69, the CDR2 sequence of SEQ ID NO:70 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:70, and the CDR3 sequence of SEQ ID NO:71 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:71;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:39 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:39, the CDR2 sequence of SEQ ID NO:40 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:40, and the CDR3 sequence of SEQ ID NO:41 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:41, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:74 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:74, the CDR2 sequence of SEQ ID NO:75 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:75, and the CDR3 sequence of SEQ ID NO:76 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:76;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:34 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:34, the CDR2 sequence of SEQ ID NO:35 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:35, and the CDR3 sequence of SEQ ID NO:36 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:36, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:74 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:74, the CDR2 sequence of SEQ ID NO:75 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:75, and the CDR3 sequence of SEQ ID NO:76 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:76;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:34 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:34, the CDR2 sequence of SEQ ID NO:35 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:35, and the CDR3 sequence of SEQ ID NO:36 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:36, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:79 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:79, the CDR2 sequence of SEQ ID NO:80 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:80, and the CDR3 sequence of SEQ ID NO:81 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:81;   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:54 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:54, the CDR2 sequence of SEQ ID NO:55 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:55, and the CDR3 sequence of SEQ ID NO:56 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:56, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66; or   a first binding arm that specifically binds to the extracellular domain of a human ErbB2 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:117 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:117, the CDR2 sequence of SEQ ID NO:118 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:118, and the CDR3 sequence of SEQ ID NO:119 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:119, and   a second binding arm that specifically binds to the extracellular domain of a human ErbB3 polypeptide and comprises a heavy chain variable region comprising the CDR1 sequence of SEQ ID NO:64 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:64, the CDR2 sequence of SEQ ID NO:65 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:65, and the CDR3 sequence of SEQ ID NO:66 or a sequence having at most two conservative amino acid substitutions relative to SEQ ID NO:66; and   the first binding arm and second binding arm each comprising a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87 or comprising CDR1, CDR2, and CDR3 sequences each having at most two conservative amino acid substitutions relative to the CDR1, CDR2, and CDR3 sequences of a light chain comprising SEQ ID NO: 87.