Methods and compositions relating to anti-CHI3L1 antibody reagents to treat nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NFALD) or metabolic syndrome
Described herein are methods and compositions relating to anti-Chi3L1 antibodies, antibody reagents, and antigen-binding fragments thereof which display superior properties, e.g., high sensitivity, high specificity, high binding affinity, neutralization activity ex vivo and in vivo (e.g., blocks Chi3L1-induced MAPK and AKT signaling). Methods of treatment, e.g., of treating cancer, obesity, and/or asthma by administering the compounds described herein are also provided.
1. A method of treating nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NFALD), or metabolic syndrome in a subject in need thereof, the method comprising administering, to the subject, a bivalent IgG antibody that specifically binds an CHI3L1 polypeptide, said bivalent IgG antibody comprising complementarity determining regions (CDRs) of:
(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 4;
(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 5;
(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 6;
(d) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 1;
(e) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 2; and
(f) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3.
2. The method of claim 1 , wherein the bivalent IgG antibody comprises a heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 or a light chain sequence having the amino acid sequence of SEQ ID NO: 38.
3. The method of claim 1 , wherein the bivalent IgG antibody comprises a heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 and a light chain sequence having the amino acid sequence of SEQ ID NO: 38.
4. The method of claim 1 , wherein bivalent IgG antibody comprises a conservative substitution relative to the heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 or the light chain sequence having the amino acid sequence of SEQ ID NO: 38, wherein the conservative substitution is in a sequence not comprised by a CDR.
5. The method of claim 1 , wherein the bivalent IgG antibody is selected from the group consisting of: a bivalent IgG which is fully humanized except for the CDR sequences; a monoclonal antibody, a CDR-grafted antibody, and a humanized antibody.
6. The method of claim 1 , wherein the bivalent IgG antibody is administered in a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.
7. The method of claim 1 , wherein the subject is a subject determined to have a level of CHI3L1 that is increased compared to a reference level from healthy subjects.
8. The method of claim 7 , wherein the CHI3L1 is circulating CHI3L1.
9. The method of claim 1 , wherein the subject is a subject determined to have a level of CHI3LI that is increased compared to the level of CHI3LI in a prior sample obtained from the subject.
10. The method of claim 9 , wherein the CHI3LI is circulating CHI3LI.