Compositions and methods for growth factor modulation

Patent metadata

Field	Value
Publication number	US-9580500-B2
Application number	US-201514795022-A
Country	US
Kind code	B2
Filing date	Jul 9, 2015
Priority date	May 6, 2013
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

Provided herein are proteins, antibodies, assays and methods useful for modulating growth factor levels and/or activities. In some embodiments, such growth factors are members of the TGF-β superfamily of proteins.

First claim

The invention claimed is:

1. A method of producing an antibody capable of binding a proTGF-β growth factor prodomain complex (GPC) comprising:
a. forming a protein complex of pro-transforming growth factor beta 1 (proTGF-β1) GPC and glycoprotein-A repetitions predominant protein (GARP);
b. utilizing the protein complex formed in (a) as a target antigen in solid-phase or solution-phase enrichment with an antibody fragment phage display library;
c. selecting phage particles that bind to the protein complex formed in (a) and which express antibody fragments on their surface, and
d. producing recombinant antibodies that bind the protein complex formed in (a) and that have complementarity determining regions (CDRs) obtained from the antibody fragments expressed at the surface of the selected phage particles of (c).

2. The method of claim 1 , further comprising:
e. conducting a negative selection binding assay of the recombinant antibodies produced in (d) to remove antibodies that bind to undesired antigens.

3. The method of claim 2 , wherein said undesired antigens are selected from the group consisting of LAP, LTBP, GARP, TGF-β1 growth factor, LAP complexed with LTBP, and LAP complexed with GARP.

4. The method of claim 2 , wherein said negative selection binding assay is selected from the group consisting of enzyme-linked immunosorbent assays, surface plasmon resonance assays and flow cytometry assays.

5. The method of claim 1 , wherein GARP comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 147-152 and 158-161.

6. The method of claim 1 , wherein phage particle binding is determined using one or more binding assays selected from the group consisting of enzyme-linked immunosorbent assays, surface plasmon resonance assays and flow cytometry assays.

7. The method of claim 1 , further comprising:
e. screening the recombinant antibodies of (d) and selecting those which reduce TGF-β growth factor activity.

8. The method of claim 7 , wherein GARP comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 147-152 and 158-161.

Assignees

• Scholar Rock Inc

Inventors

• Schurpf Thomas
• Mahanthappa Nagesh K
• Straub Michelle Marie

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title