Methods and compositions relating to anti-Chi3l1 antibody reagents
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. An antibody, antibody reagent, antigen-binding fragment thereof, or chimaeric antigen receptor (CAR), that specifically binds an CHI3L1 polypeptide, said antibody, antibody reagent, antigen-binding portion thereof, or CAR comprising the 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 antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , comprising a heavy chain sequence having the amino acid sequence of SEQ ID NO: 36.
3. The antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , comprising a light chain sequence having the amino acid sequence of SEQ ID NO: 38.
4. The antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , comprising 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.
5. The antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , further comprising 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 SED ID NO: 38, wherein the conservative substitution is in a sequence not comprised by a CDR.
6. The antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , wherein the antibody, antibody reagent, antigen-binding fragment thereof, or CAR is fully humanized except for the CDRsequences.
7. The antibody, antibody reagent, antigen-binding portion thereof, or CAR of claim 1 , wherein the antibody, antibody reagent, antigen-binding fragment thereof, or CAR is selected from the group consisting of:
an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, and a bispecific antibody.
8. A nucleic acid sequence encoding the antibody, antibody reagent, antigen-binding fragment thereof, or CAR of claim 1 .
9. The nucleic acid sequence of claim 8 , wherein at least one CDR is encoded by a nucleic acid sequence selected from SEQ ID NOs: 7-12.
10. The nucleic acid sequence of claim 8 , comprising one or more sequences selected from SEQ ID NOs: 37 and 39.
11. An isolated cell comprising the antibody, antibody reagent, antigen-binding fragment thereof, or CAR of claim 1 .
12. A pharmaceutical composition comprising the antibody, antibody reagent, antigen-binding fragment thereof, or CAR of claim 1 , and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12 , further comprising a chemotherapeutic agent.
14. The composition of claim 13 , wherein the antibody, antibody reagent, or antigen-binding portion thereof is conjugated to the chemotherapeutic agent.