Anti-psma antibodies, bispecific antigen-binding molecules that bind psma and cd3, and uses thereof

An antigen-binding molecule and bispecific technology, applied in anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, anti-animal/human immunoglobulin, etc., can solve toxicity and other problems

Active Publication Date: 2018-06-08
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These therapies have caused toxicity

Method used

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  • Anti-psma antibodies, bispecific antigen-binding molecules that bind psma and cd3, and uses thereof
  • Anti-psma antibodies, bispecific antigen-binding molecules that bind psma and cd3, and uses thereof
  • Anti-psma antibodies, bispecific antigen-binding molecules that bind psma and cd3, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] Example 1: Production of Anti-PSMA Antibodies

[0247] Resistivity is obtained by immunizing genetically modified mice with human PSMA antigen, or by immunizing engineered mice containing DNA encoding human immunoglobulin heavy chain and kappa light chain variable regions with human PSMA antigen. PSMA antibody.

[0248] Human prostate cancer cells (LNCaP, Manassas, Virginia, USA) immunized mice. After immunization, splenocytes were harvested from each mouse and either (1) fused with mouse myeloma cells to maintain their viability and form hybridomas and screened for PSMA specificity, or (2) with N-terminal 6- His-tagged human PSMA (R&D, catalog number 4234-ZN) was used as a sorting reagent for binding and identifying reactive antibodies for B cell sorting (as described in US2007 / 0280945A1) (antigen-positive B cells).

[0249] Chimeric antibodies to PSMA with human variable regions and mouse constant regions were initially isolated. Antibodies are characterized and ...

Embodiment 2

[0251] Example 2: Amino Acid and Nucleic Acid Sequences of Heavy Chain and Light Chain Variable Regions of Anti-PSMA Antibody

[0252] figure 1 Amino acid sequence identifiers for selected heavy and light chain variable regions and CDRs of anti-PSMA antibodies of the invention are set forth. The corresponding nucleic acid sequence identifiers are set forth in Table 2.

[0253] Table 1: Amino Acid Sequence Identifiers

[0254]

[0255] Table 2: Nucleic acid sequence identifiers

[0256]

Embodiment 3

[0257] Example 3: Binding affinity and kinetic constant of human monoclonal anti-PSMA antibody obtained by surface plasmon resonance

[0258] In this example, the ability of anti-PSMA antibodies to bind to human PSMA was assessed. Binding affinity and kinetic constants of anti-PSMA antibodies to soluble human PSMA protein were determined by surface plasmon resonance at 37°C using an antibody capture format. The results are shown in Tables 3 and 4. Assays were performed on a Biacore T-200 instrument (GE Healthcare).

[0259] Briefly, capture purification by amine coupling with a monoclonal mouse anti-human Fc antibody (GE, #BR-1008-39) or a monoclonal goat anti-mouse Fc antibody (GE, #BR-1008-38) Anti-PSMA antibody, derivatized CM5Biacore sensor surface. In 0.01M HEPES, 0.15M NaCl, 2mM Ca 2+ , 2mM Mg 2+ , 0.05% v / v surfactant P20pH7.4 in HBSP++ buffer for binding studies. Different concentrations of expressed human PSMA with an N-terminal hexahistidine tag (6h.hPSMA, R&D) p...

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Abstract

The present disclosure provides antibodies that bind to prostate- specific membrane antigen (PSMA), bispecific antibodies that bind to PSMA and CD3, and methods of using the same. According to certainembodiments, the antibodies of the disclosure bind human PSMA with high affinity and bind CD3 to induce human T cell proliferation. The disclosure includes antibodies that bind PSMA and CD3 and induce T cell-mediated killing of PSMA-expressing tumor cells. According to certain embodiments, the present disclosure provides bispecific antigen-binding molecules comprising a first antigen- binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human PSMA. In certain embodiments, the bispecific antigen-binding molecules of the present disclosure are capable of inhibiting the growth of prostate tumors expressing PSMA. The antibodies and bispecific antigen- binding molecules of the disclosure 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 disclosure are useful for the treatment of various cancers.

Description

[0001] Reference to Sequence Listing [0002] This application incorporates by reference the Sequence Listing, filed in computer readable form as file 10173WO01_seqlisting.txt, which was created on July 22, 2016 and contains 630,026 bytes. technical field [0003] The present invention relates to antibodies and antigen-binding fragments thereof specific for prostate-specific membrane antigen (PSMA), and methods of use thereof. The invention also relates to bispecific antigen binding molecules that bind PSMA and CD3 and methods of use thereof. Background technique [0004] Prostate-specific membrane antigen, also known as folate hydrolase 1 (FOLH1), is an integral non-shedding membrane glycoprotein that is highly expressed in prostate epithelial cells and is a cell surface marker of prostate cancer. Its expression is maintained in castration-resistant prostate cancer, a condition with poor outcome and limited treatment options. Methods of targeting PSMA to treat prostate ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30A61P35/00A61K39/395
CPCC07K16/2809A61K2039/505C07K2317/31C07K2317/33C07K2317/73C07K2317/92C07K16/3069A61P35/00A61K39/39558C07K2317/24C07K2317/56C07K2317/565C07K2317/732C07K2317/734C07K2317/76C07K2317/94
Inventor J·R·基尔什内尔A·克劳福德G·瑟斯顿E·史密斯L·哈伯D·达吉恩A·拉菲克
Owner REGENERON PHARM INC
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