Bifunctional degraders of galactose-deficient immunoglobulins

Abstract

A composition of matter including a deglycosylated IgA-binding moiety, a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) on the surface of hepatocytes or other degrading cells in a patient or subject, and optionally, a linker moiety connecting deglycosylated IgA-binding moiety and the cellular receptor-binding moiety, wherein the composition of matter is useful for removing galactose-deficient IgA1 in a patient or subject.

Description

A composition comprising a deglycosylated IgA binding portion, a cell receptor binding portion binding to hepatocytes or other degrading cells via a desialylate glycoprotein receptor (ASGPR) on the surface of hepatocytes or other degrading cells of a patient or subject, and optionally a connector portion linking the deglycosylated IgA binding portion and the cell receptor binding portion, wherein the composition can be used to remove galactose-deficient IgA1 from a patient or subject. Abstract

Claims

1. A composition of matter comprising:a galactose-deficient IgA1 (Gd-IgA1) binding moiety,a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, anda linker moiety connecting the galactose-deficient IgA1 binding moiety and the cellular receptor-binding moiety.

2. The composition of matter of Claim 1, having a structure of:[AGN101],[AGN102],[AGN103], or[AGN104]or a pharmaceutically acceptable salt thereof, wherein:each of a and b is independently an integer of 1 or greater;each AT or ABT is a galactose-deficient IgA1 binding moiety or a fragment thereof;L is a linker moiety; andeach TBT is independently a cellular receptor-binding moiety which binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface degrading cells in a patient or subject.

3. The composition of matter of Claim 2, wherein a is 1, b is 3, and each TBT comprises an N-acetyl-D-galactosamine (GalNAc) moiety.

4. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a Km55 antibody, a Km55 variant, or an antigen-binding fragment thereof.

5. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a polypeptide having complementary determining regions (CDRs) of the anti-galactose-deficient IgA1 antibody Km55.

6. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety comprises six regions according to the Kabat numbering scheme having the structures of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.

7. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a partially humanized Km55 variant or an antigen-binding fragment thereof.

8. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a chimerized Km55 variant or an antigen-binding fragment thereof.

9. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a chimerized Km55 variant or an antigen-binding fragment thereof having a heavy chain sequence comprising a LALA peptide substitution at sites L234A and L235A.

10. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 binding moiety is a chimerized Km55 variant or an antigen-binding fragment thereof having a heavy chain sequence comprising a LALA-PA peptide substitution at sites L234A, L235A, and P329A.

11. The composition of matter of Claim 1, wherein:the galactose-deficient IgA1 binding moiety comprises IgG1, or an antigen-binding fragment connected to the linker L at an amino acid residue selected from K246 and K248 of an IgG1 heavy chain and amino acid residues corresponding thereto; orwherein the galactose-deficient IgA1 binding moiety comprises IgG2 or a fragment thereof IgG2 or a fragment thereof is connected to the linker, at an amino acid residue selected from K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto; orwherein the galactose-deficient IgA1 binding moiety comprises IgG4, or an antigen-binding fragment thereof is connected to the linker, at an amino acid residue selected from K239 and K241 of an IgG4 heavy chain and amino acid residues corresponding thereto.

12. The composition of matter of Claim 11, wherein:the galactose-deficient IgA1 binding moiety comprises IgG1 and is over 90% connected to the linker L at a K248 amino acid residue as compared with any other linkage with a lysine of the antibody.

13. The composition of matter of Claim 11, wherein:the galactose-deficient IgA1 binding moiety comprises IgG1 and has two linker L at an amino acid connected to residue selected from K246 and K248 of each of the IgG1 heavy chains and amino acid residues corresponding thereto.

14. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has the polypeptide sequences of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.

15. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 1 and light chain polypeptide sequence SEQ ID NO: 2.

16. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 3 and light chain polypeptide sequence SEQ ID NO: 2.

17. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 4 and light chain polypeptide sequence SEQ ID NO: 2.

18. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 5 and light chain polypeptide sequence SEQ ID NO: 2.

19. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 6 and light chain polypeptide sequence SEQ ID NO: 2.

20. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 7 and light chain polypeptide sequence SEQ ID NO: 2.

21. The composition of matter of Claim 1, wherein the galactose-deficient IgA1 (Gd-IgA1) binding moiety has a heavy chain polypeptide sequence of SEQ ID NO: 8 and light chain polypeptide sequence SEQ ID NO: 2.

22. The composition of matter of Claim 1, wherein the linker comprises a single peptide linkage.

23. The composition of matter of Claim 1, wherein the linker comprises one or more -[(CH2)n-O]m-, wherein each n is independently 1-20, and m is 1-100.

24. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety comprises an ASGPR binding group connected through an amine group.

25. The composition of matter of Claim 1, wherein the cellular receptor-binding moiety comprises an ASGPR binding group according to the chemical structure:oror a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

26. The composition of matter of Claim 17, wherein the cellular receptor-binding moiety has the following structure:;where R^ is a C1-C3 alkyl group optionally substituted with 1-5 halo (preferably fluoro) groups (preferably R^ is a methyl or ethyl group optionally substituted with from 1-3 fluoro groups);ZA is -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG group containing from 1 to 8 preferably 1-4 ethylene glycol residues or a -C(O)(CH2)IMNRM group (preferably a PEG containing group comprising from 1 to 8 ethylene glycol, preferably 2-4 ethylene glycol residues) where IM and RM are the same as above; andZB is absent, (CH2)IM, C(O)-(CH2)IM- or C(O)-(CH2)IM-NRM, where IM and RM are the same as above.

27. The composition of matter of Claim 26, wherein the ASGPR binding group is N-acetyl-D-galactosamine.

28. A pharmaceutical composition comprising a composition of matter any of the preceding Claims 1-27 and a pharmaceutically acceptable excipient.

29. A composition comprising:a first composition of matter comprising:a galactose-deficient IgA1 (Gd-IgA1) binding moiety,a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, anda linker moiety connecting the galactose-deficient IgA1 binding moiety and the cellular receptor-binding moiety, andat least one additional composition of matter comprising:a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, anda linker moiety connecting the cellular receptor-binding moiety and capable of binding to a galactose-deficient IgA1 binding moiety.

30. A method of making a composition of matter comprising a galactose-deficient IgA1 (Gd-IgA1) binding moiety, a cellular receptor-binding moiety capable of binding to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on surface degrading cells, and a linker moiety connecting the galactose-deficient IgA1 binding moiety and the cellular receptor-binding moiety, wherein the galactose-deficient IgA1 binding moiety is a Km55 antibody, a Km55 variant, or an antigen-binding fragment thereof, comprising the steps of:(1) obtaining a Km55 variant;(2) conjugating the Km55 variant with a MATE reagent to make an amount of a composition of matter (agent).

31. The method of claim 30, wherein the amount of the composition of matter produced is 1 kg or more per production run.

32. A method of removing galactose-deficient IgA1 in a patient or subject in need comprising administering to the patient or subject an agent of any of the preceding Claims 1-27.

33. A method of treating a disease state or condition associated with the upregulation of galactose-deficient IgA1 in a patient or subject, comprising the step of:administering to the patient or subject an effective amount of an agent of any of the preceding Claims 1-2734. The method of Claim 33, wherein the disease state or condition associated with the upregulation of galactose-deficient IgA1 is an autoimmune disease.

35. The method of Claim 34, wherein the autoimmune disease is IgA nephropathy.

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