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Heterodimer binding proteins and uses thereof

A peptide heterodimer and specific binding technology, which is applied in the field of preparation and use of the polypeptide heterodimer, can solve the problem that the immunoglobulin fusion technology does not provide a heterodimeric protein production method, cannot be actively operated, and the protein does not contain And other issues

Inactive Publication Date: 2013-03-06
EMERGENT PRODUCTS DEVELOPMENT SEATTLE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the protein does not contain an Fc region and therefore cannot be actively manipulated through the Fc region
Additionally, the protein is small (~55kDa) and thus has a relatively short half-life in serum
[0012] To date, immunoglobulin fusion technology has not provided commercially available heterodimeric proteins or production methods

Method used

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  • Heterodimer binding proteins and uses thereof
  • Heterodimer binding proteins and uses thereof
  • Heterodimer binding proteins and uses thereof

Examples

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Embodiment 9 and 10）

[0217] In certain embodiments, the hinge sequence is plasma and serum stable and resistant to proteolytic cleavage. The first lysine in the upper hinge region of IgG1 can be mutated to minimize proteolytic cleavage, e.g. lysine can be replaced with methionine, threonine, alanine or glycine or deleted (see, e.g. SEQ ID NO:379-434, which may contain a linking amino acid at the amino terminus, eg RT).

[0218] In some embodiments, the hinge sequence may contain a naturally occurring or added motif capable of forming one or more disulfide bonds to stabilize the carboxy terminus of the molecule, such as the immunoglobulin hinge core structure CPPCP (SEQ ID NO:228). In other embodiments, the hinge sequence may contain one or more glycosylation sites.

[0219] Exemplary hinges, including altered immunoglobulin hinges, are shown in SEQ ID NOs: 379-434, 618-749, and 763-791.

[0220] In certain embodiments, the single-chain polypeptides of polypeptide heterodimers according to the in...

Embodiment 1

[0371] Bivalent polypeptide heterodimers containing two pairs of heterodimerization domains

[0372] The polypeptide heterodimer X0172 was generated by co-expressing single-chain polypeptides X0130 (2E12 CH1 CH2 CH3 Ck) and X0168 (Ck CH2 CH3 CH1 H68 2E12). Single-chain polypeptide X0130 contains from its amino to carboxyl terminus: 2E12 (anti-CD28) scFv, human IgG1 CH1, human IgG1 SCC-P hinge, human IgG1 CH2, human IgG1 CH3 and altered human Ck (without the first Arg or the last Cys). The nucleotide and amino acid sequences of X130 are shown in SEQ ID NO: 1 and 2, respectively. Single-chain polypeptide X0168 contains from its amino to carboxyl terminus: altered human Ck (without the first Arg or last Cys), human IgG1 SCC-P hinge, human IgG1 CH2, human IgG1 CH3, human IgG1 CH1, H68 linker and 2E12 (anti-CD28) scFv. The nucleotide and amino acid sequences of X0168 are shown in SEQ ID NO: 3 and 4, respectively. The amino acid sequence of the H68 linker is shown in SEQ ID NO:7...

Embodiment 2

[0387] Bivalent, trivalent, and tetravalent polypeptide heterodimers using a single pair of heterodimerization domains

[0388] The bivalent polypeptide heterodimer X0251 was generated by co-expressing single-chain polypeptides X0244 (Ck(YAE)CH2(N297A)CH3 H68 2E12) and X0245(2E12 CH1 CH2(N297A)CH3). The single-chain polypeptide X0244 contains from its amino to carboxyl terminus: human Ck (YAE) (for example, human Ck without the first Arg or the last Cys, but with N30Y, V55A and T70E substitutions), human IgG1 SCC-P hinge, Human IgG1 CH2(N297A) (eg, human IgG1 CH2 with N297A substitution), human IgG1 CH3, H68 linker and 2E12 (anti-CD28) scFv. The nucleic acid and amino acid sequences of X0244 are shown in SEQ ID NO: 9 and 10, respectively. The single-chain polypeptide X0245 contains from its amino to carboxyl terminus: 2E12 (anti-CD28) scFv, human IgG1 CH1, human IgG1 SCC-P hinge, human IgG1 CH2 (N297A) and human IgG1 CH3. The nucleic acid and amino acid sequences of X0245 ar...

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Abstract

The present disclosure provides polypeptide heterodimers formed between two different single chain fusion polypeptides via natural heterodimerization of an immunoglobulin CH1 region and an immunoglobulin light chain constant region (CL). The polypeptide heterodimer comprises two or more binding domains that specifically bind one or more targets (e.g., a receptor). In addition, both chains of the heterodimer further comprise an Fc region portion. The present disclosure also provides nucleic acids, vectors, host cells and methods for making polypeptide heterodimers as well as methods for using such polypeptide heterodimers, such as in directing T cell activation, inhibiting solid malignancy growth, and treating autoimmune or inflammatory conditions.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61 / 290,840, filed December 29, 2009, and U.S. Provisional Patent Application No. 61 / 365,266, filed July 16, 2010; which Each is incorporated herein by reference in its entirety. [0003] Statement Regarding Sequence Listing [0004] The relevant Sequence Listing for this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The text name containing the sequence listing is 910180_422PC_SEQUENCE_LISTING.txt. The said text file is 839KB, created on December 29, 2010, submitted electronically through EFS-Web, and submitted the application together with the instructions. [0005] background technical field [0006] The present invention generally provides polypeptide heterodimers, compositions thereof, and methods of making and using said polypeptide ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46A61K39/395A61P35/00A61P37/00
CPCC07K2317/53C07K2317/31C07K2316/52C07K16/2818C07K2317/569C07K2317/565C07K2317/21C07K2317/92C07K16/2863C07K2316/96C07K2317/56C07K16/46A61K2039/505C07K16/468C07K2317/24A61K39/395A61K45/06C07K2317/75C07K2317/622C07K2319/00C07K2317/35A61K2300/00C07K2317/64C07K2317/71A61P1/04A61P1/18A61P11/00A61P29/00A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61K38/17A61K38/18A61K47/42A61K48/00C07K14/435C07K14/475C07K16/18C07K16/28C07K19/00
Inventor J·W·布兰肯希普P·谭
Owner EMERGENT PRODUCTS DEVELOPMENT SEATTLE LLC
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