Optimized Anti-CD3 Bispecific Antibodies and Uses Thereof

a technology of bispecific antibodies and anti-cd3 is applied in the field of bispecific antibodies targeting effector antigens, which can solve the problems of inconsistent bsabs, difficult to predict differential outcomes, and high price of bsabs, and achieves reduced clearance, high affinity, and weak affinity

Inactive Publication Date: 2018-12-13
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0049]The present invention also includes the use of an anti-CD3/anti-TAA bispecific antigen-binding molecule of the invention in the manufacture of a medicament for the treatment of a disease or disorder related to or caused by TAA expression. The present invention also provides use of an anti-CD3/anti-TAA bispecific antigen-binding

Problems solved by technology

Differential outcomes are difficult to predict depending on the T cell subset being triggered to respond, as well as the state of the T cell being stimulated.
It is well-known that bsAbs do not give consistent results (Manzke O, et al.
Certain bispecific therapies have been successful, yet, as with many cancer therapies, it comes with a price.
Toxicity is the leading cause of failure among cancer therapeutics.
It is we

Method used

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  • Optimized Anti-CD3 Bispecific Antibodies and Uses Thereof
  • Optimized Anti-CD3 Bispecific Antibodies and Uses Thereof
  • Optimized Anti-CD3 Bispecific Antibodies and Uses Thereof

Examples

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example 1

n of Anti-CD3 Antibodies

[0177]The following procedures were aimed at identifying antibodies that specifically recognized CD3 (T cell co-receptor) as an antigen.

[0178]A pool of anti-CD3 antibodies were derived by immunizing genetically modified mice. Briefly, mice genetically engineered to express reverse chimeric (human variable, mouse constant) and immunoglobulin heavy chains associated with a single rearranged light chain (e.g., a VK1-39 / J or a VK3-20 / J), were immunized with a CD3 antigen and generated B cells that comprised a diversity of human VH rearrangements in order to express a diverse repertoire of high-affinity antigen-specific antibodies. Certain exemplified antibodies described in the subject application have been made recombinantly and express the same light chain sequence of VK1-39Jκ5 (LCVR set forth in SEQ ID NO: 162), while other antibodies made recombinantly express a cognate light chain of one of the heavy chain arms (e.g. the tumor target arm).

[0179]Generated ant...

example 2

Light Chain Variable Regions (Amino Acid and Nucleic Acid Sequences of the CDRs)

[0183]Amino acid and nucleic acid sequences were determined for each antibody heavy chain sequence. Each antibody heavy chain, as a derivative of the germline sequence IGHV3-9*01 / D5-12*01 / J6*02 (SEQ ID NO: 181) was assigned a “G” number designation for consistent nomenclature. Table 2 sets forth the amino acid sequence identifiers of the heavy chain variable regions and CDRs of the engineered anti-CD3 antibodies of the invention. The corresponding nucleic acid sequence identifiers are set forth in Table 3. The amino acid and nucleic acid sequence identifiers of the light chain variable region and CDRs to construct each recombinant antibody are also identified below in Tables 4 and 5, respectively.

TABLE 2Heavy Chain Amino Acid Sequence IdentifiersAntibodyCD3-VHSEQ ID NOs:DesignationHCVRCDR1CDR2CDR3CD3-VH-G2468CD3-VH-G210121416CD3-VH-G318202224CD3-VH-G426283032CD3-VH-G534363840CD3-VH-G842444648CD3-VH-G9505...

example 3

n of ULC Bispecific Antibodies that Bind CD3 and Tumor-Associated Antigens (TAA)

[0186]Bispecific antibodies comprising an anti-CD3-specific binding domain and an anti-TAA-specific binding domain, such as PSMA, EGFRvIII, MUC16, or STEAP2, were constructed using standard molecular biology methodologies utilizing a heavy chain from an anti-CD3 antibody described herein, a heavy chain from an anti-TAA antibody and a common light chain or a universal light chain (ULC). The anti-TAA antibodies used to construct the bispecific antibodies of this invention were obtained by immunizing genetically modified mice.

[0187]A summary of the component parts of the antigen-binding domains of the various bispecific antibodies made in accordance with this Example is set forth below in Tables 6, 7 and 8. All bispecific antibodies were manufactured having a modified (chimeric) IgG4 Fc domain as set forth in US Patent Application Publication No. US20140243504A1, published on Aug. 28, 2014. Exemplary EGFRvI...

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Abstract

The present invention provides antibodies that bind to CD3 with weak or no detectable binding affinity and methods of using the same. According to certain embodiments, the antibodies of the invention bind human CD3 with low affinity and induce human T cell proliferation and hence induce T cell-mediated killing of tumor cells with high efficacy. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3 with weak or no detectable binding affinity in an in vitro assay, and a second antigen-binding molecule that specifically binds human tumor-associated antigen. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing target antigen, such as PSMA. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial. For example, the antibodies of the invention are useful for the treatment of various cancers or other diseases where immunotherapy, i.e. effector cell immunomodulation is warranted.

Description

REFERENCE TO A SEQUENCE LISTING[0001]This application incorporates by reference the Sequence Listing submitted in Computer Readable Form as file 10151WO01_ST25.txt, created on Sep. 22, 2016 and containing 264,418 bytes.FIELD OF THE INVENTION[0002]The invention related to bispecific antibodies, targeting an effector antigen, such as CD3 antigen, and a tumor associated antigen, and methods of tumor killing. The invention relates to methods of reducing or eliminating tumor burden and controlling the toxic side effects that may be associated with tumor immunotherapy. The present invention provides bispecific antibodies comprising an effector arm which binds to an effector antigen with weak affinity or with no detectable binding affinity, for example, an anti-CD3 antigen-binding arm which binds to CD3 with a KD of greater than about 500 nM, in an in vitro affinity binding assay.BACKGROUND[0003]The promise of therapeutic bispecific antibodies (bsAbs), particularly in cancer immunotherapie...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/46C07K16/30C07K16/40A61P35/00
CPCC07K16/2809C07K16/468C07K16/3069C07K16/2863C07K16/40A61P35/00C07K2317/92C07K2317/31A61K2039/505C07K2317/55C07K16/28C07K2317/56C07K2317/73
Inventor SMITH, ERICHABER, LAURICBABB, ROBERTCHEN, GANGMACDONALD, DOUGLAS
Owner REGENERON PHARM INC
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