Human monoclonal antibodies to heparanase
OwnerHaichun Huang, Steven Holmes +1inventors
InventorsHaichun Huang, Steven Holmes, Sean Mason
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Abstract
Isolated human monoclonal antibodies which bind to and inhibit human heparanase, and related antibody-based compositions and molecules, are disclosed. The human antibodies can be produced by a transfectoma or in a nonhuman transgenic animal, e.g., a transgenic mouse, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are pharmaceutical compositions comprising the human antibodies, nonhuman transgenic animals and hybridomas which produce the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.
Claims33
An isolated human monoclonal antibody, or an antigen-binding portion thereof, that has the following properties:
- (a) the antibody binds to human heparanase;
- (b) the antibody inhibits enzymatic activity of human heparanase;
- (c) the antibody inhibits cell motility;
- and
- (d) the antibody inhibits tumor cell growth.
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a human heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a human light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
- (a) the human heavy chain variable region CDR3 sequence comprises SEQ ID NO:33, or conservative sequence modifications thereof ;
- (b) the human light chain variable region CDR3 sequence comprises SEQ ID NO:36, or conservative sequence modifications thereof ;
- (c) the antibody binds to human heparanase;
- (d) the antibody inhibits enzymatic activity of human heparanase;
- (e) the antibody inhibits cell motility;
- and
- (f) the antibody inhibits tumor cell growth.
An isolated human monoclonal antibody comprising:
- (a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:31, 32, and 33, respectively;
- and
- (b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:34, 35, and 36, respectively,
- wherein the antibody binds to human heparanase.
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a human heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a human light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
- (a) the human heavy chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:27, 39, 45, and 51, and conservative sequence modifications thereof ;
- (b) the human light chain variable region CDR3 sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:30, 42, 48, and 54, and conservative sequence modifications thereof ;
- (c) the antibody binds to human heparanase;
- (d) the antibody inhibits enzymatic activity of human heparanase;
- (e) the antibody inhibits cell motility;
- and
- (f) the antibody inhibits tumor cell growth.
An isolated human monoclonal antibody selected from the group consisting of :
- (a) an antibody comprising (i) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:25, 26, and 27, respectively;
- and (ii) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:
- 28, 29, and 30, respectively, wherein the antibody binds to human heparanase;
- (b) an antibody comprising (i) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:37, 38, and 39, respectively;
- and (ii) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:
- 40, 41, and 42, respectively, wherein the antibody binds to human heparanase;
- (c) an antibody comprising (i) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:43, 44, and 45, respectively;
- and (ii) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:
- 46, 47, and 48, respectively, wherein the antibody binds to human heparanase;
- and
- (d) an antibody comprising (i) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:49, 50, and 51, respectively;
- and (ii) a light chain variable region~comprising CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs:
- 52, 53 and 54, respectively, wherein the antibody binds to human heparanase;
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a human heavy chain variable region and a human light chain variable region, wherein:
- (a) the human heavy chain variable region comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:6;
- (b) the human light chain variable region comprises an amino acid sequence that is at least 90% homologous to the amino acid sequence of SEQ ID NO:8;
- (c) the antibody binds to human heparanase;
- (d) the antibody inhibits enzymatic activity of human heparanase;
- (e) the antibody inhibits cell motility;
- and
- (f) the antibody inhibits tumor cell growth.
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising human heavy chain and human light chain variable regions comprising the amino acid sequences shown in SEQ ID NO:6 and SEQ ID NO:8, respectively.
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a human heavy chain variable region and a human light chain variable region, wherein:
- (a) the human heavy chain variable region comprises an amino acid sequence that is at least 90% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 10, 14, and 18;
- (b) the human light chain variable region comprises an amino acid sequence that is at least 90% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 4, 12, 16, and 20;
- (c) the antibody binds to human heparanase;
- (d) the antibody inhibits enzymatic activity of human heparanase;
- (e) the antibody inhibits cell motility;
- and
- (f) the antibody inhibits tumor cell growth.
An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a human heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 10, 14, and 18 and a human light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 4, 12, 16, and 20.
An isolated human monoclonal antibody comprising:
- (a) a heavy chain variable region derived from a human VH1-24 germline sequence (SEQ ID NO:21);
- and
- (b) a light chain variable region derived from a human VκL15 (SEQ ID NO:23) germline sequence;
- wherein the human antibody binds human heparanase.
An isolated human monoclonal antibody comprising:
- (a) a heavy chain variable region derived from a human VH3-07 germline sequence (SEQ ID NO:22);
- and
- (b) a light chain variable region derived from a human VκL18 germline sequence (SEQ ID NO:24);
- wherein the human antibody binds to human heparanase.
Dependencies are inferred from the claim text.