Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics

A technology of human monoclonal antibody and monoclonal antibody, applied in anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody medical components, anti-animal/human immunoglobulin, etc., can solve the lack of MYPPPY Motif and other issues

Active Publication Date: 2008-07-02
ONO PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although structurally similar to CTLA-4, PD-1 lacks

Method used

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  • Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
  • Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
  • Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0578] Example 1: Generation of human monoclonal antibodies against PD-1

[0579] antigen

[0580] The immunization protocol utilizes as antigens both (i) a recombinant fusion protein comprising the extracellular portion of PD-1, and (ii) membrane-bound full-length PD-1. Both antigens were produced in CHO cell lines by recombinant transfection methods.

[0581] Transgenic HuMab and KM mice TM

[0582] Fully human monoclonal antibodies against PD-1 were prepared using the HCo7 strain of HuMab transgenic mice and the KM strain of transgenic transchromosomal mice, both of which express human antibody genes. In each of these mouse strains, the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820, and as described in PCT Publication WO The homozygosity described in Example 1 of 01 / 09187 disrupts the endogenous mouse heavy chain gene. Each of these mouse strains carries the human kappa light chain tran...

Embodiment 2

[0591] Example 2: Structural characterization of human monoclonal antibodies 17D8, 2D3, 4H1, 5C4, 4A11, 7D3 and 5F4

[0592] DNA encoding the heavy and light chain variable regions of the 17D8, 2D3, 4H1, 5C4, 4A11, 7D3, and 5F4 monoclonal antibodies were obtained from 17D8, 2D3, 4H1, 5C4, 4A11, 7D3, and 5F4 hybridomas, respectively, using standard PCR techniques. cDNA sequences and were sequenced using standard DNA sequencing techniques.

[0593] The nucleotide and amino acid sequences of the heavy chain variable region of 17D8 are shown in Figure 1A and SEQ ID NO:57 and 1.

[0594] The nucleotide and amino acid sequences of the light chain variable region of 17D8 are shown in Figure 1B and SEQ ID NO:64 and 8.

[0595] Comparison of the 17D8 heavy chain immunoglobulin sequence with known human germline immunoglobulin heavy chain sequences indicates that the 17D8 heavy chain utilizes a VH segment from human germline VH 3-33, an undetermined D segment, and a D segment from g...

Embodiment 3

[0621] Example 3: Characterization of Binding Specificity and Binding Kinetics of Anti-PD-1 Human Monoclonal Antibodies

[0622] In this example, the binding affinity and binding kinetics of anti-PD-1 antibodies were examined by Biacore analysis. Binding specificity and cross-competition were examined by flow cytometry.

[0623] Binding affinity and kinetics

[0624] Anti-PD-1 antibodies were characterized for affinity and binding kinetics by Biacore analysis (Biacore AB, Uppsala, Sweden). Purified recombinant human PD-1 fusion protein was covalently attached to a CM5 chip (carboxymethyl dextran-coated chip) via a primary amine using standard amine coupling chemistry and kits provided by Biacore. Binding was measured by flowing the antibody in HBS EP buffer (provided by Biacore AB) at a concentration of 267 nM at a flow rate of 50 μl / min. Antigen-antibody binding kinetics were followed for 3 minutes and dissociation kinetics were followed for 7 minutes. Association and d...

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Abstract

The present invention provides isolated monoclonal antibodies, particularly human monoclonal antibodies, that specifically bind to PD-1 with high affinity. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for detecting PD-1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-1 antibodies. The present invention further provides methods for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer. The invention also provides methods for altering adverse events related to treatment with such antibodies individually.

Description

technical field [0001] In general, the present invention relates to immunotherapies for treating human disease and reducing associated adverse events. More specifically, the invention relates to the use of anti-PD-1 antibodies and combination immunotherapy comprising anti-CTLA-4 antibodies in combination with anti-PD-1 antibodies to treat cancer and / or reduce the risk of cancer associated with treatment with such antibodies alone. The incidence or severity of adverse events. Background of the invention [0002] The protein programmed death 1 (PD-1) is an inhibitory member of the CD28 receptor family, which also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed on activated B cells, T cells, and myeloid cells (Agata et al., supra; Okazaki et al. (2002) Curr. Opin. Immunol. 14:391779-82; Bennett et al. (2003) J Immunol 170:711-8). The original members of the family, CD28 and ICOS (Hutloff et al. (1999) Nature 397: 263-266; Hansen et al. (1999) Immunogenics 10: 247-260...

Claims

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Application Information

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IPC IPC(8): C12N15/09C07K16/28C12N5/00C12P21/08C12Q1/02
CPCA61K2039/505C07K2317/21C07K2317/24C07K2317/56C07K2317/565C07K2317/732C07K2317/52C07K2317/74C07K2317/75C07K2317/76A61K47/6849A61P7/06C07K2317/73C07K16/2818Y02A50/30C07K16/28A61K39/39533A61K39/39558A61K51/10C07K16/18C07K16/468A61K39/3955A61K39/00A61K2039/507C07K16/2803C07K2317/33C07K2317/92C07K2317/94
Inventor 艾伦·J·科曼莫汉·斯里尼瓦森王常玉马克·J·塞尔比陈炳良约瑟芬·M·卡达雷里
Owner ONO PHARMA CO LTD
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