Antagonistic human light-specific human monoclonal antibodies
Provided herein are antibodies that immunospecifically bind to an hLIGHT polypeptide; isolated nucleic acids encoding the antibodies; vectors and host cells comprising nucleic acids encoding the antibodies; methods of making the antibodies; and a method of treating a hLIGHT-mediated disease in a subject comprising administering to the subject the antibodies. In preferred embodiments, the anti-hLIGHT antibodies provided herein will ameliorate, neutralize or otherwise inhibit hLIGHT biological activity in vivo (e.g., the hLIGHT-mediated production or secretion of CCL20, IL-8 or RANTES from a cell expressing a hLIGHT receptor). Also provided herein is a method for the detection of hLIGHT in a sample as well as a method for ameliorating, neutralizing or otherwise inhibiting hLIGHT activity, e.g., in a human subject suffering from a disorder in which hLIGHT activity is detrimental.
1. An isolated antibody,
(a) characterized by having six complementarity determining regions (CDRs) of antibody F19 or antibody F23 and a framework region having an amino acid sequence of at least 85% sequence identity to the framework region of the variable region of antibody F19 or antibody F23; and
(b1) characterized by exhibiting binding specificity for an epitope of hLIGHT, wherein said binding is blocked by:
(i) an antibody produced by hybridoma ATCC Accession No. PTA-7819, or
(ii) an antibody produced by hybridoma ATCC Accession No. PTA-7728, with the proviso that the binding to the epitope of hLIGHT is not blocked by both of:
(iii) an antibody produced by hybridoma ATCC Accession No. PTA-7729 and an antibody produced by hybridoma ATCC Accession No. PTA-7842,
(iv) an antibody produced by hybridoma ATCC Accession No. PTA-7729 and an antibody produced by hybridoma ATCC Accession No. PTA-7818, or
(v) an antibody produced by hybridoma ATCC Accession No. PTA-7842 and an antibody produced by hybridoma ATCC Accession No. PTA-7818; or
(b2) characterized by being fully human and exhibiting binding specificity for an epitope of hLIGHT, wherein said binding is blocked by:
(i) an antibody produced by hybridoma ATCC Accession No. PTA-7819, or
(ii) an antibody produced by hybridoma ATCC Accession No. PTA-7728.
2. The isolated antibody of claim 1 , wherein the binding is blocked in a dose-dependent manner.
3. The isolated antibody of claim 1 , wherein the antibody is an antagonist antibody.
4. The isolated antibody of claim 3 , wherein
(a) the antibody competes with HVEM, LTβR, or a fusion protein thereof, for binding to cell surface-expressed hLIGHT or soluble hLIGHT;
(b) the antibody partially or completely inhibits binding of HVEM, LTβR, DcR3, or any combination thereof, to cell surface-expressed hLIGHT or soluble hLIGHT; or
(c) the antibody partially or completely inhibits hLIGHT-mediated secretion of CCL20, IL-8, RANTES, or any combination thereof, from a cell having a cell surface-expressed hLIGHT receptor.
5. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a heavy chain variable region (VH) of an antibody produced by hybridoma ATCC Accession No. PTA-7819 or hybridoma ATCC Accession No. PTA-7728;
(b) a light chain variable region (VL) of an antibody produced by hybridoma ATCC Accession No. PTA-7819 or hybridoma ATCC Accession No. PTA-7728; or
(c) a VH of an antibody produced by hybridoma ATCC Accession No. PTA-7819 or hybridoma ATCC Accession No. PTA-7728, and a VL of an antibody produced by hybridoma ATCC Accession No. PTA-7819 or hybridoma ATCC Accession No. PTA-7728.
6. The isolated antibody of claim 1 , wherein the isolated antibody is an antibody produced by hybridoma ATCC Accession No. PTA-7819 or an antibody produced by hybridoma ATCC Accession No. PTA-7728.
7. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a VH selected from (i) amino acids 20-141 of SEQ ID NO:4 and (ii) amino acids 27-143 of SEQ ID NO:5;
(b) a VL selected from (i) amino acids 23-129 of SEQ ID NO:90, (ii) amino acids 23-129of SEQ ID NO:91, (iii) amino acids 21-126 of SEQ ID NO:92, (iv) amino acids 23-129 of SEQ ID NO:9, and (v) amino acids 23-129 of SEQ ID NO:10; or
(c) a VH selected from (i) amino acids 20-141 of SEQ ID NO:4 and (ii) amino acids 27-143 of SEQ ID NO:5; and a VL selected from (i) amino acids 23-129 of SEQ ID NO:90, (ii) amino acids 23-129 of SEQ ID NO:91, (iii) amino acids 21-126 of SEQ ID NO:92, (iv) amino acids 23-129 of SEQ ID NO:9, and (v) amino acids 23-129 of SEQ ID NO:10.
8. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a VH comprising:
(i) a VH CDR1 as set forth in SEQ ID NO:20,
(ii) a VH CDR2 as set forth in SEQ ID NO:21, and
(iii) a VH CDR3 as set forth in SEQ ID NO:22;
and a VL comprising:
(i) a VL CDR1 selected from the group consisting of SEQ ID NOs:93, 35, 94, and 95,
(ii) a VL CDR2 selected from the group consisting of SEQ ID NOs:96, 36, 97, and 98, and
(iii) a VL CDR3 selected from the group consisting of SEQ ID NOs:99, 37, 100, and 101; or
(b) a VH comprising:
(i) a VH CDR1 as set forth in SEQ ID NO:23,
(ii) a VH CDR2 as set forth in SEQ ID NO:24, and
(iii) a VH CDR3 as set forth in SEQ ID NO:25,
and a VL comprising:
(i) a VL CDR1 as set forth in SEQ ID NO:38,
(ii) a VL CDR2 as set forth in SEQ ID NO:39, and
(iii) a VL CDR3 as set forth in SEQ ID NO:40.
9. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a VH encoded by a nucleotide sequence that hybridizes under stringent conditions to the complement of a nucleotide sequence set forth in any one of SEQ ID NOs:44 and 45;
(b) a VL encoded by a nucleotide sequence that hybridizes under stringent conditions to the complement of a nucleotide sequence set forth in any one of SEQ ID NOs:104, 49, 105, 106 and 50; or
(c) a VH encoded by a nucleotide sequence that hybridizes under stringent conditions to the complement of a nucleotide sequence set forth in any one of SEQ ID NOs:44 and 45, and a VL encoded by a nucleotide sequence that hybridizes under stringent conditions to the complement of a nucleotide sequence set forth in any one of SEQ ID NOs:104, 49, 105, 106 and 50, wherein said stringent conditions comprise hybridizing in 6x sodium chloride/sodium citrate (SSC) at about 45° C., and washing in 0.2xSSC/0.1% SDS at about 50-65° C.
10. The isolated antibody of claim 1 , wherein the antibody is an IgG antibody.
11. The isolated antibody of claim 10 , wherein the antibody is an IgG1 antibody or an IgG4 antibody.
12. The isolated antibody of claim 1 , wherein the antibody is selected from the group consisting a fully human antibody, a chimeric or humanized antibody, an antigen binding fragment, a Fab fragment, a F(ab’)2 fragment, a single chain Fv (sFv) antibody, a diabody, or a triabody.
13. The isolated antibody of claim 1 , wherein the antibody is a monoclonal antibody or a recombinant antibody.
14. A pharmaceutical composition comprising an antibody of claim 1 .
15. A hybridoma that produces an antibody as recited in claim 1 .
16. The hybridoma of claim 15 , wherein the hybridoma is hybridoma ATCC Accession No. PTA-7819 or hybridoma ATCC Accession No. PTA-7728.
17. A kit comprising an antibody of claim 1 .
18. The isolated antibody of claim 1 , wherein the variable region of antibody F19 comprises amino acids 20-141 of the amino acid sequence set forth in SEQ ID NO:4 and amino acids 23-129 of the amino acid sequence set forth in SEQ ID NO:9, and wherein the variable region of antibody F23 comprises amino acids 27-143 of the amino acid sequence set forth in SEQ ID NO:5 and amino acids 23-129 of the amino acid sequence set forth in SEQ ID NO:10.