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ANTI-PD-1 antibodies, activatable ANTI-PD-1 antibodies, and methods of use thereof

A PD-1 and antibody technology, applied in chemical instruments and methods, antibodies, antibody medical components, etc., can solve problems such as deterioration

Active Publication Date: 2018-08-03
CYTOMX THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since similar mechanisms govern antitumor immunity and self-tolerance, systemic delivery of these checkpoint-targeted therapies may also induce Systemic autoimmunity exacerbated by ipilimumab (anti-CTLA4)

Method used

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  • ANTI-PD-1 antibodies, activatable ANTI-PD-1 antibodies, and methods of use thereof
  • ANTI-PD-1 antibodies, activatable ANTI-PD-1 antibodies, and methods of use thereof
  • ANTI-PD-1 antibodies, activatable ANTI-PD-1 antibodies, and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0905] Example 1. Generation of mouse antibodies of embodiments that bind to human PD-1 and block hPD-L1 and hPD-L2 binding to human PD-1

[0906] This example demonstrates that mouse antibodies of the invention that bind to human PD-1 can be isolated from hybridomas derived from mice immunized with recombinant human PD-1 protein, and that such binding can inhibit PD-1 binding to PDL1 and PDL2.

[0907] Six NZBWF1 / J female mice (Jackson Laboratories, Sacramento, CA; cat. no. 100008) were immunized on the right side with recombinant human PD-1 (Sino Biological, Beijing, P.R. China; cat. no. ABIN2181605) on days 0, 7, and 21 ). Sera were taken from immunized mice on day 28 and binding to HEK293-hPD-1 (cells transfected with an expression vector encoding human PD-1 (Origene, cat. no. SC117011)) was measured. All six mice showed positive binding. Splenocytes were isolated from mice 1, 3, and 6 and fused with SPO mouse B cells; similarly, splenocytes were isolated from mice 2, 4,...

Embodiment 2

[0920] Example 2. Purification and testing of humanized anti-PD-1 antibodies

[0921] This example demonstrates that mouse antibodies of the invention that bind human PD-1 can be converted into humanized IgG antibodies that retain PD-1 binding and inhibition of PDL1 and PDL2 binding to PD-1.

[0922] The variable domains of mouse anti-PD-1 antibodies generated as described in Example 1 were humanized and expressed as full-length hIgG4 / hκ antibodies. Fully human IgG anti-PD-1 antibodies were expressed from transiently transfected HEK-293 cells and purified from culture supernatants by protein A chromatography.

[0923] The humanized antibody sequences used in the studies presented here are as follows:

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[0935] These variable heavy chain regions (VH) and variable light chain regions (VL) can be used in various combinations to generate anti-PD-1 ant...

Embodiment 3

[0937] Example 3: Anti-PD-1 antibodies show specificity in binding

[0938] Example 3 shows that humanized anti-PD-1 antibody groups A1 and C1 of the present invention specifically bind hPD-1 by plate ELISA.

[0939]Binding of the anti-PD-1 antibody A1.5 of the present invention is highly specific for hPD-1-Fc against a panel of numerous human and mouse proteins in a standard ELISA ( Figure 10 ). Binding of anti-PD-1 A1.5 was detected with an anti-human IgG-HRP conjugate (specific for FAb) (Sigma, StLouis, MO) and visualized with the chromogenic substrate TMB (Thermo Scientific, Rockford, IL). Plot in Prizm (Sigma Plot) and fit the data to a model for single site saturation binding.

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Abstract

The invention relates generally to antibodies that specifically bind programmed cell death protein 1 (PD-1), activatable antibodies that specifically bind to PD-1 and methods of making and using theseanti-PD-1 antibodies and anti-PD-1 activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.

Description

[0001] Related applications [0002] This application claims U.S. Provisional Application No. 62 / 191,902, filed Jul. 13, 2015; U.S. Provisional Application No. 62 / 205,825, filed Aug. 17, 2015; U.S. Provisional Application, filed Feb. 15, 2016 U.S. Provisional Application No. 62 / 323,543, filed April 15, 2016; and U.S. Provisional Application No. 62 / 333,629, filed May 9, 2016; the contents of each of which are in their entirety Incorporated herein by reference. Field of Invention [0003] The present invention generally relates to antibodies that specifically bind programmed cell death protein 1 (PD-1), activatable antibodies that specifically bind PD-1, and the preparation of these anti-PD-1 antibodies and anti-PD-1 activatable antibodies and in multiple methods for their use in therapeutic, diagnostic and prophylactic indications. Background of the Invention [0004] Antibody-based therapies have proven to be effective treatments for several diseases, but in some cases tox...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395A61K39/00
CPCC07K16/2818C07K2317/24C07K2317/54C07K2317/55C07K2317/56C07K2317/565C07K2317/569C07K2317/622C07K2317/76C07K2317/92C07K2319/50A61K2039/505A61K2039/507A61K2039/545A61K47/6849A61P35/00A61P37/04A61P43/00C07K16/30C07K16/3046C07K16/3053C07K16/3069C07K16/303C07K16/3015A61K39/3955C07K16/3023C07K16/3038
Inventor K.A.蒂普顿J.W.韦斯特C.M.陈
Owner CYTOMX THERAPEUTICS
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