Composition and methods of treating inflammatory and autoimmune diseases
OwnerKunwar SHAILUBHAIinventor
Life of this patent
Estimating the term…
Abstract
This invention relates to methods of treating disorders such as celiac disease by administrating anti-CD3 antibodies alone or in combination with additional agents.
Claims48
A method for treating a disorder comprising administering an oral dosage form of an anti-CD3 antibody and a compound that improves gut barrier function and/or an anti-inflammatory compound.
The method of any one of the preceding claims, wherein the compound that improves gut barrier function reduces gut permeability.
The method of any one of the preceding claims, wherein the compound that improves gut barrier function is a retinoic acid, a GC-C receptor agonist, heparin, lubiprostone, glutamine, GLP-2 peptide, a zolulin peptide inhibitor, a zonulin antagonist, larazotide, a probiotic bacteria or butyric acid.
The method of any one of the preceding claims, wherein the GC-C receptor agonist is administered at a daily dose of about 1 to about 10 mg.
The method of any one of the preceding claims, wherein the GC-C receptor agonist is administered at a daily dose of 3 mg or 6 mg.
The method of any one of the preceding claims, wherein the GC-C agonist is administered once daily.
The method of anyone of the preceding claims, wherein the anti-CD3 antibody is fully human, humanized or murine.
The method of any one of the preceding claims, wherein the anti-CD3 antibody administered at a daily dose of about 0.1 mg to about 10 mg.
The method of any one of the preceding claims, wherein the anti-CD3 antibody is administered for a treatment cycle of 30 days.
The method of any one of the preceding claims, wherein the anti-CD3 antibody is administered for a treatment cycle comprising an on period of 15 days and an off period of 15 days.
The method of any one of the preceding claims, wherein the anti-CD3 antibody and the compound that increases gut barrier function are administered for a treatment cycle of 30 days.
The method of any one of the preceding claims, wherein the anti-CD3 antibody and the compound that increases gut barrier function are administered for a treatment cycle, the treatment cycle comprising an on period of 15 days and an off period of 15 days for the anti-CD3 antibody and an on period of 30 days for the compound that increases gut barrier function.
The method of any one of the preceding claims, wherein the anti-CD3 antibody, the compound that increases gut barrier function and the GC-C receptor agonist, are administered for a treatment cycle or 30 days.
The method of any one of the preceding claims, wherein the anti-CD3 antibody, the compound that increases gut barrier function and the GC-C receptor agonist, are administered for a treatment cycle, the treatment cycle comprising an on period of 15 days and an off period of 15 days for the anti-CD3 antibody or antigen-binding fragment thereof, an on period of 30 days for the GC-C agonist, and an on period of 30 days for the retinoic acid.
The method of any one of the preceding claims, wherein the oral dosage form of the anti-CD3 antibody is an enteric polymer-coated oral dosage form.
The method of any of the proceeding claims, wherein the anti-CD3 antibody comprises:
- (i) a heavy chain comprising a variable heavy chain complementarity determining region 1 (VH CDR1) comprising the amino acid sequence of GYGMH (SEQ ID NO:
- 1), a variable heavy chain complementarity determining region 2 (VH CDR2) comprising the amino acid sequence of VIWYDGSKKYYVDSVKG (SEQ ID NO:
- 2), a variable heavy chain complementarity determining region 3 (VH CDR3) comprising the amino acid sequence of QMGYWHFDL (SEQ ID NO:
- 3);
- and a light chain comprising a variable light chain complementarity determining region 1 (VL CDR1) comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO:
- 4), a variable light chain complementarity determining region 2 (VL CDR2) comprising the amino acid sequence of DASNRAT (SEQ ID NO:
- 5), a variable light chain complementarity determining region 3 (VL CDR3) comprising the amino acid sequence of QQRSNWPPLT (SEQ ID NO:
- 6);
- (ii) a heavy chain comprising a VH CDR1 comprising the amino acid sequence SYGMH (SEQ ID NO:
- 7);
- a VH CDR2 comprising the amino acid sequence of IIWYDGSKKNYADSVKG (SEQ ID NO:
- 8);
- a VH CDR3 comprising the amino acid sequence of GTGYNWFDP (SEQ ID NO:
- 9);
- and a light chain comprising a VL CDR1 comprising the amino acid sequence of RASQSVSSSYLA (SEQ ID NO:
- 10), RASQGISSALA (SEQ ID NO:
- 11) or WASQGISSYLA (SEQ ID NO:
- 12);
- a VL CDR2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:
- 13), YASSLQS (SEQ ID NO:
- 14), or DASSLGS (SEQ ID NO:
- 15);
- and a VL CDR3 comprising the amino acid sequence of QQYGSSPIT (SEQ ID NO:
- 16) or QQYYSTLT (SEQ ID NO:
- 17);
- and
- (iii) a heavy chain comprising a VH CDR1 comprising the amino acid sequence SYGMH (SEQ ID NO:
- 7);
- a VH CDR2 comprising the amino acid sequence of AIWYNGRKQDYADSVKG (SEQ ID NO:
- 18);
- a VH CDR3 comprising the amino acid sequence of GTGYNWFDP (SEQ ID NO:
- 9);
- and a light chain comprising a VL CDR1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO:
- 4) or RASQGISSALA (SEQ ID NO:
- 11);
- a VL CDR2 comprising the amino acid sequence of DASNRAT (SEQ ID NO:
- 5) or DASSLES (SEQ ID NO:
- 19);
- and a VL CDR3 comprising the amino acid sequence of QQRSNWPWT (SEQ ID NO:
- 20) or QQFNSYPIT (SEQ ID NO:
- 21).
The method of any of the proceeding claims, wherein the anti-CD3 antibody o comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NOs:
- 22 (28F11 VH), 24 (23F10 VH), 26 (27H5 VH), or 32 (15C3 VH), and a light chain variable region (VL) having the amino acid sequence of SEQ ID NOs:
- 23 (28F11 VL), 25 (23F10 VL), 27 (27H5 VL1), 28 (27H5 VL2), 29 (27H5 VL3), 30 (27H5 VL4), 31 (27H5 VL5), 33 (15C3 VL1), or 34 (15C3 VL2).
The method of any one of the preceding claims, wherein the anti-CD3 antibody or antigen-binding fragment thereof comprises a framework 2 region (FWR2) comprising the amino acid sequence WVRQAPGKGLEWV (SEQ ID NO:
- 35).
The method of any one of the preceding claims, wherein the anti-CD3 antibody or antigen-binding fragment thereof comprises a framework 3 region (FRW3) comprising the amino acid sequence RFTISRDNSKNTLYLQMNSLRAEDTAVYYCA (SEQ ID NO:36).
The method of any one of the preceding claims, wherein the anti-CD3 antibody is an IgG1 isotype.
The method of any one of the preceding claims, wherein the anti-CD3 antibody or antigen-binding fragment thereof includes a mutation in the heavy chain at an amino acid residue at position 234, 235, 265, or 297 or combinations thereof, and reduces the release of cytokines from a T cell, wherein the amino acid residue positions are numbered according to Kabat
Dependencies are inferred from the claim text.