Targeted therapeutics based on engineered proteins for tyrosine kinases receptors, including IGF-IR

Patent metadata

Field	Value
Publication number	US-11149077-B2
Application number	US-201916244851-A
Country	US
Kind code	B2
Filing date	Jan 10, 2019
Priority date	Nov 22, 2006
Publication date	Oct 19, 2021
Grant date	Oct 19, 2021

Abstract

The present invention provides innovative proteins that bind to insulin-like growth factor-I receptor (IGF-IR), as well as other important proteins. The invention also provides innovative proteins in pharmaceutical preparations and derivatives of such proteins and the uses of same in diagnostic, research and therapeutic applications. The invention further provides cells comprising such proteins, polynucleotide encoding such proteins or fragments thereof, and vectors comprising the polynucleotides encoding the innovative proteins.

First claim

The invention claimed is:

1. A polypeptide comprising a single-tenth fibronectin type III ( 10 Fn3) domain, wherein the 10 Fn3 domain is an altered 10 Fn3 domain which (i) comprises a loop, AB; a loop, BC; a loop, CD; a loop, DE; a loop, EF; and a loop, FG; (ii) has at least one loop selected from loop BC, DE, and FG with an altered amino acid sequence relative to the sequence of the corresponding loop of the human 10 Fn3 domain having the amino acid sequence of SEQ ID NO: 1, and (iii) binds human IGF-IR with a disassociation constant of about 1 μM or less,
wherein the polypeptide comprises at most one 10 Fn3 domain, and
wherein the altered 10 Fn3 domain comprises an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 2-125.

2. The polypeptide of claim 1 , wherein the 10 Fn3 domain binds human IGF-IR with a disassociation constant of about 10 nM or less.

3. The polypeptide of claim 1 , wherein loop BC and loop FG have an altered amino acid sequence relative to the sequence of the corresponding loop of the human 10 Fn3 domain.

4. The polypeptide of claim 1 , wherein the 10 Fn3 domain comprises the amino acid sequence of any of one of SEQ ID NOs: 2-125.

5. The polypeptide of claim 1 , further comprising one or more pharmacokinetic (PK) moieties selected from: a polyoxyalkylene moiety, a human serum albumin binding protein, sialic acid, human serum albumin, transferrin, and an Fc fragment.

6. The polypeptide of claim 5 , wherein the PK moiety is a polyoxyalkylene moiety and said polyoxyalkylene moiety is polyethylene glycol.

7. The polypeptide of claim 1 , wherein said polypeptide inhibits the binding of IGF-I or IGF-II to IGF-IR and does not activate human IGF-IR at sub IC50 concentrations in a cell-based assay.

8. A pharmaceutically acceptable composition comprising the polypeptide of claim 1 , wherein the composition is essentially endotoxin free.

9. The polypeptide of claim 1 , wherein the altered 10 Fn3 domain comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 2-125.

10. The polypeptide of claim 1 , wherein the altered 10 Fn3 domain comprises an amino acid sequence that is at least 95% identical to any one of SEQ ID NOs: 2-125.

Assignees

• Bristol Myers Squibb Co

Inventors

• Camphausen Ray
• Fabrizio David
• Wright Martin C
• Gage Patrick
• Mendlein John

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K14/78 Primary

  Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG] · CPC title

• C12N15/10

  Processes for the isolation, preparation or purification of DNA or RNA (chemical preparation of DNA or RNA C07H21/00; preparation of non-structural polynucleotides from microorganisms or with enzymes C12P19/34) · CPC title

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C12N15/1062

  mRNA-Display, e.g. polypeptide and encoding template are connected covalently · CPC title