Anti-MET Antibodies and Methods of Use Thereof

Abstract

Provided herein are compositions, methods and uses involving antibodies that specifically bind to MET, a receptor tyrosine kinase, and modulate the expression and/or activity of MET. Also provided are uses and methods for managing, treating, or preventing disorders, such as cancer. In one aspect, provided herein is a monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of human MET. Also provided herein is a kit comprising an antibody or antigen-binding fragment provided herein. Also provided herein is a method of managing, protecting against, or treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment provided herein.

What is claimed: 
     
         1 . A monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of human MET, wherein the antibody or antigen-binding fragment thereof:
 a. inhibits MET activity in cells as determined by inhibition of phosphorylation of MET;   b. induces MET degradation in cells; and   c. inhibits tumor cell proliferation or tumor growth; and   wherein the antibody inhibits phosphorylation of MET, induces MET degradation, or inhibits tumor cell proliferation or tumor growth better as a human IgG 2  isotype as compared to as an IgG 1  isotype.   
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a light chain variable region (VL) comprising VL complementary determining region 1 (CDR1), VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab237, Ab239, or Ab241-Ab255 as set forth in Table 1; and   b. a heavy chain variable region (VH) comprising VH complementary determining region 1 (CDR1), VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab237, Ab239, or Ab241-Ab255 as set forth in Table 2.   
     
     
         3 . The antibody or antigen-binding fragment of  claim 2 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 265, 5, and 6, respectively. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 2 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 7, 8, and 9, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 266, 11, and 12, respectively. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 2 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 13, 14, and 15, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 16, 17, and 18, respectively. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 2 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 25, 26, and 27, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 28, 73, and 29, respectively. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 2 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 72, 14, and 15, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 16, 73, and 18, respectively. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SASSSVX 7 YMF (SEQ ID NO:41), wherein X 7  is any amino acid, for example, N or S; 
 ii. a VL CDR2 comprising the amino acid sequence of DTX 13 X 14 LAS (SEQ ID NO:43), wherein X 13  is any amino acid, for example, F or S and X 14  is any amino acid, for example, N or D; 
 iii. a VL CDR3 comprising the amino acid sequence of QQWSX 15 YPYT (SEQ ID NO:44), wherein X 15  is any amino acid, for example, I or N; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence X 1 YWIEW (SEQ ID NO:36), wherein X 1  is any amino acid, for example, N or S; 
 ii. a VH CDR2 comprising the amino acid sequence of EILPGSDX 3 TKYX 4 EKFKGK (SEQ ID NO:38), wherein X 3  is any amino acid, for example, Y or F and X 4  is any amino acid, for example, N or S; and 
 iii. a VH CDR3 comprising the amino acid sequence of PSTX 6 PPDC (SEQ ID NO:40), wherein X 6  is any amino acid, for example, I or V. 
   
     
     
         9 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43  is any amino acid, for example, T or A, X 44  is any amino acid, for example, N or S, X 45  is any amino acid, for example, A or P, X 46  is any amino acid, for example, F or S, X 47  is any amino acid, for example, N or D, and X 48  is any amino acid, for example, I or N. 
     
     
         10 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCWG QGTTLTVSA (SEQ ID NO:50), wherein X 57  is any amino acid, for example, V or A, X 58  is any amino acid, for example, I or T, X 59  is any amino acid, for example, N or S, X 60  is any amino acid, for example, Y or F, X 61  is any amino acid, for example, T or I, X 62  is any amino acid, for example, N or S, X 63  is any amino acid, for example, S or N, and X 64  is any amino acid, for example, I or V. 
     
     
         11 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43  is any amino acid, for example, T or A, X 44  is any amino acid, for example, N or S, X 45  is any amino acid, for example, A or P, X 46  is any amino acid, for example, F or S, X 47  is any amino acid, for example, N or D, and X 48  is any amino acid, for example, I or N; and   b. a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCWG QGTTLTVSA (SEQ ID NO:50), wherein X 57  is any amino acid, for example, V or A, X 58  is any amino acid, for example, I or T, X 59  is any amino acid, for example, N or S, X 60  is any amino acid, for example, Y or F, X 61  is any amino acid, for example, T or I, X 62  is any amino acid, for example, N or S, X 63  is any amino acid, for example, S or N, and X 64  is any amino acid, for example, I or V.   
     
     
         12 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:57. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:57; and   b. a VH comprising the amino acid sequence of SEQ ID NO:66.   
     
     
         15 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:58. 
     
     
         16 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67. 
     
     
         17 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:58; and   b. a VH comprising the amino acid sequence of SEQ ID NO:67.   
     
     
         18 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SEQ ID NOS: 13 or 72; 
 ii. a VL CDR2 comprising the amino acid sequence of SEQ ID NO:14; 
 iii. a VL CDR3 comprising the amino acid sequence of SEQ ID NO:15; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence of SEQ ID NOS: 16, 28, or DX 2 YMA (SEQ ID NO:37), wherein X 2  is any amino acid, for example, S or C; 
 ii. a VH CDR2 comprising the amino acid sequence of SEQ ID NOS: 17 or 46, or SISSDGGGTYYRDSVKGX 5  (SEQ ID NO:39), wherein X 5  is any amino acid, for example, R or is absent; and 
 iii. a VH CDR3 comprising the amino acid sequence of SEQ ID NOS: 18 or 29, or EX 16 X 17 YX 18 X 19 X 20 YYX 21 X 22 X 23 FX 24 X 25  (SE ID NO:45), wherein X 16  is any amino acid, for example, G or R, X 17  is any amino acid, for example, I or Y, X 18  is any amino acid, for example, T or D, X 19  is any amino acid, for example, T or G, X 20  is any amino acid, for example, D or T, X 21  is any amino acid, for example, P or G, X 22  is any amino acid, for example, C or W, X 23  is any amino acid, for example, Y or absent, X 24  is any amino acid, for example, N or D, and X 25  is any amino acid, for example, Y or F. 
   
     
     
         19 . The antibody or antigen-binding fragment of  claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25; 
 ii. a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26; 
 iii. a VL CDR3 comprising the amino acid sequence of SEQ ID NO:27; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence of SEQ ID NOS: 16, 28, or DX 2 YMA (SEQ ID NO:37), wherein X 2  is any amino acid, for example, S or C; 
 ii. a VH CDR2 comprising the amino acid sequence of SEQ ID NOS: 17 or 46, or SISSDGGGTYYRDSVKGX 5  (SEQ ID NO:39), wherein X 5  is any amino acid, for example, R or is absent; and 
 iii. a VH CDR3 comprising the amino acid sequence of SEQ ID NOS: 18 or 29, or EX 16 X 17 YX 18 X 19 X 20 YYX 21 X 22 X 23 FX 24 X 25  (SE ID NO:45), wherein X 16  is any amino acid, for example, G or R, X 17  is any amino acid, for example, I or Y, X 18  is any amino acid, for example, T or D, X 19  is any amino acid, for example, T or G, X 20  is any amino acid, for example, D or T, X 21  is any amino acid, for example, P or G, X 22  is any amino acid, for example, C or W, X 23  is any amino acid, for example, Y or absent, X 24  is any amino acid, for example, N or D, and X 25  is any amino acid, for example, Y or F. 
   
     
     
         20 . The antibody or antigen-binding fragment thereof of  claim 1 ,
 wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGNN LNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGTK LEIK (SEQ ID NO:47), wherein X 26  is any amino acid, for example, S or G, X 27  is any amino acid, for example, V or L, X 28  is any amino acid, for example, D or E, X 29  is any amino acid, for example, R or T, X 30  is any amino acid, for example, T or E, X 31  is any amino acid, for example, K or N, X 32  is any amino acid, for example, A or S, X 33  is any amino acid, for example, K or Q, X 34  is any amino acid, for example, F or S, X 35  is any amino acid, for example, F or S, X 36  is any amino acid, for example, D or Q, X 37  is any amino acid, for example, F or Y, X 38  is any amino acid, for example, T or S, X 39  is any amino acid, for example, T or K, X 40  is any amino acid, for example, S or N, X 41  is any amino acid, for example, P or S, and X 42  is any amino acid, for example, A or S.   
     
     
         21 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDGG GTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYCF NYWGX 54 GX 55 MVTVSX 56  (SEQ ID NO:49), wherein X 49  is any amino acid, for example, G or R, X 50  is any amino acid, for example, G or T, X 51  is any amino acid, for example, T or S, X 52  is any amino acid, for example, S or N, X 53  is any amino acid, for example, T or S, X 54  is any amino acid, for example, Q or H, X 55  is any amino acid, for example, V or T, and X 56  is any amino acid, for example, S or A. 
     
     
         22 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGNN LNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGTK LEIK (SEQ ID NO:47), wherein X 26  is S or G, X 27  is V or L, X 28  is D or E, X 29  is R or T, X 30  is T or E, X 31  is K or N, X 32  is A or S, X 33  is K or Q, X 34  is F or S, X 35  is F or S, X 36  is D or Q, X 37  is F or Y, X 38  is T or S, X 39  is T or K, X 40  is S or N, X 41  is P or S, and X 42  is A or S; and   b. a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDGG GTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYCF NYWGX 54 GX 55 MVTVSX 56  (SEQ ID NO:49, wherein X 49  is any amino acid, for example, G or R, X 50  is any amino acid, for example, G or T, X 51  is any amino acid, for example, T or S, X 52  is any amino acid, for example, S or N, X 53  is any amino acid, for example, T or S, X 54  is any amino acid, for example, Q or H, X 55  is any amino acid, for example, V or T, and X 56  is any amino acid, for example, S or A.   
     
     
         23 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:59. 
     
     
         24 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:52. 
     
     
         25 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:53. 
     
     
         26 . The antibody or antigen-binding fragment of  claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:54. 
     
     
         27 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:55. 
     
     
         28 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:56. 
     
     
         29 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:61. 
     
     
         30 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68. 
     
     
         31 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63. 
     
     
         32 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64. 
     
     
         33 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65. 
     
     
         34 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70. 
     
     
         35 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:59; and   b. a VH comprising the amino acid sequence of SEQ ID NO:68.   
     
     
         36 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         37 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         38 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         39 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         40 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         41 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         42 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         43 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         44 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         45 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         46 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         47 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         48 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         49 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         50 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         51 . The antibody or antigen-binding fragment of  claim 22 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:61; and   b. a VH comprising the amino acid sequence of SEQ ID NO:70.   
     
     
         52 . The antibody or antigen binding fragment thereof of any one of  claims 1 - 51  specifically binds to human MET and monkey MET, but not mouse MET or dog MET. 
     
     
         53 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 52 , wherein the inhibition of MET activity occurs in SNU-5 cells, A549 cells, and/or Hop92 cells. 
     
     
         54 . The antibody or antigen-binding fragment thereof of  claim 53 , wherein the IC 50  for the inhibition of MET activity in SNU-5 cells is between about 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM. 
     
     
         55 . The antibody or antigen-binding fragment thereof of  claim 53 , wherein the maximal percent inhibition of MET activity in SNU-5 cells that is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 
     
     
         56 . The antibody or antigen-binding fragment thereof of  claim 55 , wherein the IgG 2  isotype has a maximal percent inhibition of MET activity in SNU-5 cells that is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold more than the maximal percent inhibition of MET activity of the IgG 1  isotype. 
     
     
         57 . The antibody or antigen-binding fragment thereof of  claim 53 , wherein the IC 50  for the inhibition of MET activity in A549 cells is between about 40 pM to about 250 pM, 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM. 
     
     
         58 . The antibody or antigen-binding fragment thereof of  claim 53 , wherein the IC 50  for the inhibition of MET activity in Hop92 cells is between about 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM. 
     
     
         59 . The antibody or antigen-binding fragment thereof of  claim 57 , wherein the IC 50  for the inhibition of MET activity in Hop92 cells is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than a humanized anti-MET antibody that does not bind the SEMA domain or a bivalent, IgG 4  anti-MET antibody that binds to the SEMA domain. 
     
     
         60 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 59 , wherein the phosphorylation of MET is determined at MET amino acid residues Tyr1234 and/or Tyr1235. 
     
     
         61 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 60 , wherein the induction of MET degradation occurs in SNU-5 cells, A549 cells, U87MG cells, H596 cells, Hop92 cells, or in tumor cells. 
     
     
         62 . The antibody or antigen-binding fragment thereof of  claim 61 , wherein the maximal percent induction of MET degradation in SNU-5 cells is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 
     
     
         63 . The antibody or antigen-binding fragment thereof of  claim 61 , wherein the IgG 2  isotype maximal percent induction of MET degradation in the SNU-5 cells is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold more than the IgG 1  isotype maximal percent induction of MET degradation. 
     
     
         64 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 63 , wherein the inhibition of tumor cell proliferation occurs in SNU-5 tumor cells, EBC-1 tumor cells, U87MG tumor cells, A549 tumor cells, and/or H596 tumor cells. 
     
     
         65 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the maximal percent inhibition for the inhibition of the SNU-5 tumor cell proliferation is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 
     
     
         66 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the IgG 2  isotype maximal percent inhibition for the inhibition of the SNU-5 tumor cell proliferation is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold higher than the IgG 1  maximal percent inhibition. 
     
     
         67 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the maximal percent inhibition for the inhibition of the EBC-1 tumor cell proliferation is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 
     
     
         68 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the IgG 2  isotype maximal percent inhibition for the inhibition of the EBC-1 tumor cell proliferation is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold higher than the IgG 1  maximal percent inhibition. 
     
     
         69 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the IC 50  for the inhibition of tumor cell proliferation in the U87MG tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM. 
     
     
         70 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the IC 50  for the inhibition of tumor cell proliferation in the A549 tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM. 
     
     
         71 . The antibody or antigen-binding fragment thereof of  claim 64 , wherein the IC 50  for the inhibition of tumor cell proliferation in the H596 tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM. 
     
     
         72 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 71 , wherein the tumor growth is a U87 xenograft tumor model, a SNU15 xenograft tumor model, or a U87MG orthotopic tumor model. 
     
     
         73 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 72 , which inhibits the interaction between MET and hepatocyte growth factor (HGF) on cells. 
     
     
         74 . The antibody or antigen-binding fragment thereof of  claim 73 , wherein the cells are A549 cells. 
     
     
         75 . The antibody or antigen-binding fragment thereof of  claim 74 , wherein the IC 50  for the inhibition of the interaction between MET and HGF on the A549 cells is between about 0.01 nM to 10,000 nM, 0.01 nM to 1,000 nM, 0.1 nM to 500 nM, 0.1 nM to 100 nM, or 0.1 nM to 50 nM. 
     
     
         76 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 75 , which induces ubiquitination of MET in cells. 
     
     
         77 . The antibody or antigen-binding fragment thereof of  claim 76 , wherein the cells are A549 cells. 
     
     
         78 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 77 , which inhibits MET signaling in cells. 
     
     
         79 . The antibody or antigen-binding fragment thereof of  claim 78 , wherein the MET signaling is HGF-dependent. 
     
     
         80 . The antibody or antigen-binding fragment thereof of  claim 78 , wherein the MET signaling is HGF-independent. 
     
     
         81 . The antibody or antigen-binding fragment thereof of any one of  claims 78 - 80 , wherein the inhibition of MET signaling is identified as inhibition of AKT and/or MET phosphorylation. 
     
     
         82 . The antibody or antigen-binding fragment thereof of any one of  claims 78 - 81 , wherein the cells are A549 cells. 
     
     
         83 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 82 , which inhibits HGF-induced endothelial to mesenchymal transition (EMT). 
     
     
         84 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 83 , wherein the inhibition of HGF-induced EMT is determined by DU145 cell scatter. 
     
     
         85 . The antibody or antigen-binding fragment thereof of  claim 84 , wherein the IC 50  for the DU145 cell scatter is about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001 nM. 
     
     
         86 . The antibody or antigen-binding fragment thereof of  claim 84  or  85 , wherein the DU145 cell scatter is percent inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%. 
     
     
         87 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 86 , wherein the IgG 2  isotype of the antibody alters MET dimer configuration as compared to the IgG 1  isotype of the antibody. 
     
     
         88 . A monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of MET, wherein the antibody or antigen-binding fragment thereof comprises:
 a. a light chain variable region (VL) comprising VL complementary determining region 1 (CDR1), VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 1; and   b. a heavy chain variable region (VH) comprising VH complementary determining region 1 (CDR1), VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 2.   
     
     
         89 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 265, 5, and 6, respectively. 
     
     
         90 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 7, 8, and 9, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 266, 11, and 12, respectively. 
     
     
         91 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 13, 14, and 15, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 16, 17, and 18, respectively. 
     
     
         92 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 19, 20, and 21, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 267, 23, and 24, respectively. 
     
     
         93 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 25, 26, and 27, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 28, 73, and 29, respectively. 
     
     
         94 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 72, 14, and 15, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 16, 73, and 18, respectively. 
     
     
         95 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 30, 31, and 32, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 33, 34, and 35, respectively. 
     
     
         96 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 13 or 72; 
 ii. a VL CDR2 comprising the amino acid sequence of SEQ ID NO:14; 
 iii. a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 15; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence of SEQ ID NOS: 16, 28, or DX 2 YMA (SEQ ID NO:37), wherein X 2  is any amino acid, for example, S or C; 
 ii. a VH CDR2 comprising the amino acid sequence of SEQ ID NOS: 17 or 46, or SISSDGGGTYYRDSVKGX 5  (SEQ ID NO:39), wherein X 5  is any amino acid, for example, R or is absent; and 
 iii. a VH CDR3 comprising the amino acid sequence of SEQ ID NOS: 18 or 29, or EX 16 X 17 YX 18 X 19 X 20 YYX 21 X 22 X 23 FX 24 X 25  (SE ID NO:45), wherein X 16  is any amino acid, for example, G or R, X 17  is any amino acid, for example, I or Y, X 18  is any amino acid, for example, T or D, X 19  is any amino acid, for example, T or G, X 20  is any amino acid, for example, D or T, X 21  is any amino acid, for example, P or G, X 22  is any amino acid, for example, C or W, X 23  is any amino acid, for example, Y or absent, X 24  is any amino acid, for example, N or D, and X 25  is any amino acid, for example, Y or F. 
   
     
     
         97 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SEQ ID NO:25; 
 ii. a VL CDR2 comprising the amino acid sequence of SEQ ID NO:26; 
 iii. a VL CDR3 comprising the amino acid sequence of SEQ ID NO:27; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence of SEQ ID NOS: 16, 28, or DX 2 YMA (SEQ ID NO:37), wherein X 2  is any amino acid, for example, S or C; 
 ii. a VH CDR2 comprising the amino acid sequence of SEQ ID NOS: 17 or 46, or SISSDGGGTYYRDSVKGX 5  (SEQ ID NO:39), wherein X 5  is any amino acid, for example, R or is absent; and 
 iii. a VH CDR3 comprising the amino acid sequence of SEQ ID NOS: 18 or 29, or EX 16 X 17 YX 18 X 19 X 20 YYX 21 X 22 X 23 FX 24 X 25  (SE ID NO:45), wherein X 16  is any amino acid, for example, G or R, X 17  is any amino acid, for example, I or Y, X 18  is any amino acid, for example, T or D, X 19  is any amino acid, for example, T or G, X 20  is any amino acid, for example, D or T, X 21  is any amino acid, for example, P or G, X 22  is any amino acid, for example, C or W, X 23  is any amino acid, for example, Y or absent, X 24  is any amino acid, for example, N or D, and X 25  is any amino acid, for example, Y or F. 
   
     
     
         98 . The antibody or antigen-binding fragment of  claim 88 , wherein the VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequences of SEQ ID NOS: 19, 20, and 21, respectively, and the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequences of SEQ ID NOS: 267, 23, and 24, respectively. 
     
     
         99 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGNN LNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGTK LEIK (SEQ ID NO:47), wherein X 26  is any amino acid, for example, S or G, X 27  is any amino acid, for example, V or L, X 28  is any amino acid, for example, D or E, X 29  is any amino acid, for example, R or T, X 30  is any amino acid, for example, T or E, X 31  is any amino acid, for example, K or N, X 32  is any amino acid, for example, A or S, X 33  is any amino acid, for example, K or Q, X 34  is any amino acid, for example, F or S, X 35  is any amino acid, for example, F or S, X 36  is any amino acid, for example, D or Q, X 37  is any amino acid, for example, F or Y, X 38  is any amino acid, for example, T or S, X 39  is any amino acid, for example, T or K, X 40  is any amino acid, for example, S or N, X 41  is any amino acid, for example, P or S, and X 42  is any amino acid, for example, A or S. 
     
     
         100 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDGG GTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYCF NYWGX 54 GX 55 MVTVSX 56  (SEQ ID NO:49, wherein X 49  is any amino acid, for example, G or R, X 50  is any amino acid, for example, G or T, X 51  is any amino acid, for example, T or S, X 52  is any amino acid, for example, S or N, X 53  is any amino acid, for example, T or S, X 54  is any amino acid, for example, Q or H, X 55  is any amino acid, for example, V or T, and X 56  is any amino acid, for example, S or A. 
     
     
         101 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGNN LNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGTK LEIK (SEQ ID NO:47), wherein X 26  is any amino acid, for example, S or G, X 27  is any amino acid, for example, V or L, X 28  is any amino acid, for example, D or E, X 29  is any amino acid, for example, R or T, X 30  is any amino acid, for example, T or E, X 31  is any amino acid, for example, K or N, X 32  is any amino acid, for example, A or S, X 33  is any amino acid, for example, K or Q, X 34  is any amino acid, for example, F or S, X 35  is any amino acid, for example, F or S, X 36  is any amino acid, for example, D or Q, X 37  is any amino acid, for example, F or Y, X 38  is any amino acid, for example, T or S, X 39  is any amino acid, for example, T or K, X 40  is any amino acid, for example, S or N, X 41  is any amino acid, for example, P or S, and X 42  is any amino acid, for example, A or S; and   b. a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDGG GTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYCF NYWGX 54 GX 55 MVTVSX 56  (SEQ ID NO:49, wherein X 49  is any amino acid, for example, G or R, X 50  is any amino acid, for example, G or T, X 51  is any amino acid, for example, T or S, X 52  is any amino acid, for example, S or N, X 53  is any amino acid, for example, T or S, X 54  is any amino acid, for example, Q or H, X 55  is any amino acid, for example, V or T, and X 56  is any amino acid, for example, S or A.   
     
     
         102 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:59. 
     
     
         103 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:52. 
     
     
         104 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:53. 
     
     
         105 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:54. 
     
     
         106 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:55. 
     
     
         107 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:56. 
     
     
         108 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:61. 
     
     
         109 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:60. 
     
     
         110 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68. 
     
     
         111 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63. 
     
     
         112 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64. 
     
     
         113 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65. 
     
     
         114 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70. 
     
     
         115 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:69. 
     
     
         116 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:59; and   b. a VH comprising the amino acid sequence of SEQ ID NO:68.   
     
     
         117 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         118 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         119 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         120 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         121 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:63.   
     
     
         122 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         123 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         124 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         125 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         126 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:64.   
     
     
         127 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:52; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         128 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:53; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         129 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:54; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         130 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:55; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         131 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:56; and   b. a VH comprising the amino acid sequence of SEQ ID NO:65.   
     
     
         132 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:61; and   b. a VH comprising the amino acid sequence of SEQ ID NO:70.   
     
     
         133 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:60; and   b. a VH comprising the amino acid sequence of SEQ ID NO:69.   
     
     
         134 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising:
 i. a VL CDR1 comprising the amino acid sequence of SASSSVX 7 YMF (SEQ ID NO:41), wherein X 7  is any amino acid, for example, N or S; 
 ii. a VL CDR2 comprising the amino acid sequence of DTX 13 X 14 LAS (SEQ ID NO:43), wherein X 13  is any amino acid, for example, F or S and X 14  is any amino acid, for example, N or D; 
 iii. a VL CDR3 comprising the amino acid sequence of QQWSX 15 YPYT (SEQ ID NO:44), wherein X 15  is any amino acid, for example, I or N; and 
   b. a VH comprising:
 i. a VH CDR1 comprising the amino acid sequence X 1 YWIEW (SEQ ID NO:36), wherein X 1  is any amino acid, for example, N or S; 
 ii. a VH CDR2 comprising the amino acid sequence of EILPGSDX 3 TKYX 4 EKFKGK (SEQ ID NO:38), wherein X 3  is any amino acid, for example, Y or F and X 4  is any amino acid, for example, N or S; and 
 iii. a VH CDR3 comprising the amino acid sequence of PSTX 6 PPDC (SEQ ID NO:40), wherein X 6  is any amino acid, for example, I or V. 
   
     
     
         135 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43  is any amino acid, for example, T or A, X 44  is any amino acid, for example, N or S, X 45  is any amino acid, for example, A or P, X 46  is any amino acid, for example, F or S, X 47  is any amino acid, for example, N or D, and X 48  is any amino acid, for example, I or N. 
     
     
         136 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCWG QGTTLTVSA (SEQ ID NO:50), wherein X 57  is any amino acid, for example, V or A, X 58  is any amino acid, for example, I or T, X 59  is any amino acid, for example, N or S, X 60  is any amino acid, for example, Y or F, X 61  is any amino acid, for example, T or I, X 62  is any amino acid, for example, N or S, X 63  is any amino acid, for example, S or N, and X 64  is any amino acid, for example, I or V. 
     
     
         137 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43  is any amino acid, for example, T or A, X 44  is any amino acid, for example, N or S, X 45  is any amino acid, for example, A or P, X 46  is any amino acid, for example, F or S, X 47  is any amino acid, for example, N or D, and X 48  is any amino acid, for example, I or N; and   b. a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCWG QGTTLTVSA (SEQ ID NO:50), wherein X 57  is any amino acid, for example, V or A, X 58  is any amino acid, for example, I or T, X 59  is any amino acid, for example, N or S, X 60  is any amino acid, for example, Y or F, X 61  is any amino acid, for example, T or I, X 62  is any amino acid, for example, N or S, X 63  is any amino acid, for example, S or N, and X 64  is any amino acid, for example, I or V.   
     
     
         138 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:57. 
     
     
         139 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66. 
     
     
         140 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:57; and   b. a VH comprising the amino acid sequence of SEQ ID NO:66.   
     
     
         141 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:58. 
     
     
         142 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67. 
     
     
         143 . The antibody or antigen-binding fragment of  claim 88 , wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:58; and   b. a VH comprising the amino acid sequence of SEQ ID NO:67.   
     
     
         144 . An isolated antibody or antigen-binding fragment thereof that binds to the Sema domain of MET, wherein the antibody or antigen-binding fragment thereof comprises:
 a. a light chain variable region (VL) comprising VL complementary determining region 1 (CDR1), VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 5; and   b. a heavy chain variable region (VH) comprising VH complementary determining region 1 (CDR1), VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 6.   
     
     
         145 . An isolated antibody or antigen-binding fragment thereof that binds to the Sema domain of MET, wherein the antibody or antigen-binding fragment thereof comprises:
 a. a light chain variable region (VL) comprising VL complementary determining region 1 (CDR1), VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 7; and   b. a heavy chain variable region (VH) comprising VH complementary determining region 1 (CDR1), VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab255 as set forth in Table 8.   
     
     
         146 . A monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of MET, wherein the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:62. 
     
     
         147 . A monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of MET, wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:71. 
     
     
         148 . A monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of MET, wherein the antibody or antigen-binding fragment thereof comprises:
 a. a VL comprising the amino acid sequence of SEQ ID NO:62; and   b. a VH comprising the amino acid sequence of SEQ ID NO:71.   
     
     
         149 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 148 , which inhibits metastasis. 
     
     
         150 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 149 , wherein the antibody comprises a human IgG constant region. 
     
     
         151 . The antibody or antigen-binding fragment thereof of  claim 150 , wherein the antibody comprises a human IgG 2  constant region. 
     
     
         152 . The antibody or antigen-binding fragment thereof of  claim 150 , wherein the antibody comprises a human IgG 2a  constant region. 
     
     
         153 . The antibody or antigen-binding fragment thereof of  claim 150 , wherein the antibody comprises a human IgG 2b  constant region. 
     
     
         154 . The antibody or antigen-binding fragment thereof of  claim 150 , wherein the antibody comprises a mixture of a human IgG 2a  constant region and a human IgG 2b  constant region. 
     
     
         155 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 149 , wherein the antibody comprises a human IgG 2  Fc region. 
     
     
         156 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 155 , wherein the antibody comprises a human kappa light chain constant region. 
     
     
         157 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 155 , wherein the antibody comprises a human lambda light chain constant region. 
     
     
         158 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 157 , wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         159 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 158 , wherein the antibody is a bispecific antibody or antigen-binding fragment thereof. 
     
     
         160 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 159 , wherein the antibody or antigen-binding fragment thereof is fused to a heterologous polypeptide. 
     
     
         161 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 157 , wherein the humanized antibody is a deimmunized antibody or a composite human antibody. 
     
     
         162 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 161 , wherein the antibody or the antigen-binding fragment thereof is conjugated to an agent. 
     
     
         163 . The antibody or antigen-binding fragment thereof of  claim 162 , wherein the agent is suitable for imaging and therapy. 
     
     
         164 . The antibody or antigen-binding fragment thereof of  claim 162  or  163 , wherein the agent is a radioisotope, quantum dots, or other nano-particles. 
     
     
         165 . The antibody or antigen-binding fragment thereof of  claim 162 , wherein the agent is a toxin. 
     
     
         166 . The antibody or antigen-binding fragment thereof of  claim 165 , wherein the toxin is abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin. 
     
     
         167 . An antibody of any one of  claims 1 - 166 . 
     
     
         168 . A composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any one of  claims 1 - 166 . 
     
     
         169 . A composition comprising a therapeutically effective amount of the antibody of  claim 167 . 
     
     
         170 . The composition of  claim 168  further comprising a pharmaceutically acceptable carrier. 
     
     
         171 . The composition of  claim 169  further comprising a pharmaceutically acceptable carrier. 
     
     
         172 . A polynucleotide comprising nucleotide sequences encoding a VH chain region, a VL chain region, or both a VL chain region and a VH chain region, of an antibody of any one of  claims 1 - 166 . 
     
     
         173 . A polynucleotide comprising nucleotide sequences encoding a heavy chain, a light chain, or both heavy chain and a light chain of an antibody of any one of  claims 1 - 166 . 
     
     
         174 . The polynucleotide of  claim 172  or  173 , wherein the polynucleotide is operably linked to a promoter. 
     
     
         175 . A population of polynucleotides comprising (i) a first polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of the antibody of any one of  claims 1 - 166 , and (ii) a second polypeptide comprising nucleotide sequences encoding a VL or a light chain of the antibody of any one of  claims 1 - 166 . 
     
     
         176 . The population of polynucleotides of  claim 175 , wherein the first polynucleotide is operably linked to a first promoter, and wherein the second polynucleotide is operably linked to a second promoter. 
     
     
         177 . A vector comprising the polynucleotide of any of  claims 172 - 174 . 
     
     
         178 . A population of vectors comprising (i) a first vector comprising nucleotide sequences encoding a VH or a heavy chain of the antibody of any one of  claims 1 - 166 , and (ii) a second vector comprising nucleotide sequences encoding a VL or a light chain of the antibody of any one of  claims 1 - 166 . 
     
     
         179 . A population of vectors comprising (i) a first vector comprising nucleotide sequences encoding a VH or a heavy chain of the antibody of any one of  claims 1 - 166  operably linked to a first promoter, and (ii) a second vector comprising nucleotide sequences encoding a VL or a light chain of the antibody of any one of  claims 1 - 166  operably linked to a second promoter. 
     
     
         180 . A cell comprising the polynucleotide of any one of  claims 172 - 174 . 
     
     
         181 . A cell comprising the population of polynucleotides of  claim 175  or  176 . 
     
     
         182 . A cell comprising the vector of  claim 177 . 
     
     
         183 . A cell comprising the population of vectors of  claim 178  or  179 . 
     
     
         184 . An isolated cell producing the antibody or antigen-binding fragment of any one of  claims 1 - 166 . 
     
     
         185 . A population of cells comprising (i) a first host cell comprising a polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of the antibody of any one of  claims 1 - 166 , and (ii) a second host cell comprising a polynucleotide comprising nucleotide sequences encoding a VL or a light chain of the antibody of any one of  claims 1 - 166 . 
     
     
         186 . A population of cells comprising (i) a first host cell comprising a polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of the antibody of any one of  claims 1 - 166  operably linked to a first promoter, and (ii) a second host cell comprising a polynucleotide comprising nucleotide sequences encoding a VL or a light chain of the antibody of any one of  claims 1 - 166  operably linked to a second promoter. 
     
     
         187 . A kit comprising the antibody or antigen-binding fragment of any one of  claims 1 - 166 . 
     
     
         188 . A method of managing, protecting against, or treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody or antigen-binding fragment of any one of  claims 1 - 166 . 
     
     
         189 . A method of managing, protecting against, or treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of  claims 168 - 171 . 
     
     
         190 . The method of  claim 188  or  189 , wherein the cancer is colorectal, gastric, lung, melanoma, uveal melanoma, non-small cell lung, stomach, esophagus, brain, liver, kidney, head and neck, thyroid, ovary, prostate, pancreas, breast, colon, oral, muscular, bone, glioma, or lymphoid cancer. 
     
     
         191 . A method of managing, preventing, protecting against, or treating metastasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the antibody or antigen-binding fragment of any one of  claims 1 - 166 . 
     
     
         192 . A method of managing, preventing, protecting against, or treating metastasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of  claims 168 - 171 . 
     
     
         193 . The method of any one of  claims 188 - 192 , wherein the patient expresses a MET comprising one or more deletions in exon 14 of the human MET gene. 
     
     
         194 . The method of any one of  claims 188 - 192 , wherein the patient expresses a MET protein comprising an isoleucine amino acid substitution at MET amino acid residue Thr1010. 
     
     
         195 . The method of any one of  claims 188 - 194 , wherein the subject has cancer, or is being treated for cancer with an anti-cancer therapeutic. 
     
     
         196 . The method of any one of  claims 188 - 195 , wherein the cancer comprises cancer cells expressing MET. 
     
     
         197 . The method of any one of  claims 188 - 196 , wherein the cancer comprises cancer cells expressing EGFR. 
     
     
         198 . The method of any one of  claims 188 - 197 , further comprising administering to the patient another agent. 
     
     
         199 . The method of  claim 198 , wherein the agent is a chemotherapeutic agent. 
     
     
         200 . The method of any one of  claims 188 - 199 , wherein the method is a method of managing. 
     
     
         201 . The method of any one of  claims 188 - 199 , wherein the method is a method of treating. 
     
     
         202 . A method of making an antibody or an antigen-binding fragment thereof which specifically binds to the Sema domain of human MET, comprising culturing the cell or population of cells of any one of  claims 180 - 186  to express the antibody or antigen-binding fragment. 
     
     
         203 . A method of making an antibody or an antigen-binding fragment thereof which specifically binds to the Sema domain of human MET, comprising expressing the polynucleotide of any one of  claims 172 - 176 .