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Use of Anti-human sirpa v1 antibodies and method for producing Anti-sirpa v1 antibodies

A technology of antibodies and antigens, applied in chemical instruments and methods, anti-animal/human immunoglobulins, antibodies, etc., can solve problems such as lack of distinction between SIRP families

Pending Publication Date: 2020-12-18
OSE IMMUNOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Therefore, the antibodies described in the prior art lack the ability to discriminate between the individual members of the SIRP family, and there is a need for more specific antibodies; in particular, antibodies for the prevention or treatment of several diseases

Method used

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  • Use of Anti-human sirpa v1 antibodies and method for producing Anti-sirpa v1 antibodies
  • Use of Anti-human sirpa v1 antibodies and method for producing Anti-sirpa v1 antibodies
  • Use of Anti-human sirpa v1 antibodies and method for producing Anti-sirpa v1 antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0302] Example 1: Identification of epitopes capable of producing anti-human SIRPa v1 antibodies

[0303]It was previously described that human SIRPα exhibits a certain degree of polymorphism in domain 1 of IgV that interacts with CD47. This polymorphism is mainly located in exon 3 of the SIRPa gene (SEQ ID NO: 27) (Takenaka et al., 2007). identified 10 distinct sequences / alleles in genome sequences from 37 different donors from different sources, including 2 major alleles: variant 1 (v1) and variant 2 (v2) . Other alleles differed by only 1 or 2 SNPs from the V1 or V2 sequence. Thus, the SIRPa family can be subdivided into two subfamilies: the SIRPa v1 isoform and the SIRPa v2 isoform. These different alleles result in slightly different proteins, but all variants bind the CD47 ligand similarly. In the article by Takenaka et al., the v1 allele frequency was 78% (V1-like was 89%), while the genotype frequency of homozygous V1 / V1-like donors was 65%. 24% of their 37 dono...

Embodiment 2

[0333] Example 2: Comparison of the effect of blockade of the SIRPa-CD47 interaction between mice and humans on immune cross-presentation

[0334] Mouse cross-presentation ( Figure 5 )

[0335] Drugs: An allosteric antagonistic monoclonal antibody targeting mouse SIRPα domain 2 (P84 clone – rat IgG1) was purified from a hybridoma. An orthosteric antagonistic monoclonal antibody targeting mouse SIRPα domain 1 (clone MY-1 – mouse IgG2a) (Garcia et al., 2011) was reengineered to the IgG1 Fc domain of the parental hybridoma. Both anti-SIRPα antibodies blocked signaling through SIRPα in myeloid cells. Isotype control mouse IgGl (clone 3G8) was purified. A surrogate antagonist anti-mouse CD47 monoclonal antibody (MIAP410 clone) was purchased from BioXCell (#BE0283).

[0336] Expression of mouse SIRPa by splenic DC: Native DC were isolated from spleens of naive mice by CD11c-positive magnetic separation, and their CD8α expression was isolated by BD FACS ARIA II cell sorting....

Embodiment 3

[0353] Example 3: Effect of SIRP / CD47 Blockade on Polyclonal Stimulation

[0354] Methods: hPBMC were isolated from the buffy coat of healthy volunteers. CD4 or CD8 T cells were screened by positive selection using AutoMACS (Miltenyi) and plated in 96-well plates (50000 cells / well). Proliferation signals were provided by anti-CD3 / anti-CD28 coated microbeads (Life Technologies) (at a ratio of 1 microbead:1 T cell) over a period of 3 days, or by allogeneic mature dendritic cells generated in vitro ( 5T cells: 1 mDC) were provided over a period of 5 days. Starting from the proliferation assay, antibodies targeting the SIRPa / CD47 and / or SIRPg / CD47 pathways were added at saturating concentrations (10 μg / mL). By incorporation of H during the last 12 hours of culture 3 -thymidine to measure proliferation. Anti-CD47 antibody (commercially available reference number: B6H12), anti-SIRPa antibody (HEFLB, as described in patent WO2017178653).

[0355] Results: To study the immunosu...

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Abstract

The invention is in the field of immunotherapy. The present invention provides antibodies useful in therapeutic and diagnostic applications targeting human SIRPa, said antibodies enhancing the cross-presentation of antigens to T cells. The invention also provides antibodies against specific isoforms of SIRP a and able to disrupt the interaction between those isoforms of SIRP a and human CD47 for use in treating or preventing a disease, or diagnostic applications, and methods for producing and / or selecting anti-human SIRPa antibodies that bind with different affinities to various isoforms of human SIRP members.

Description

technical field [0001] The invention belongs to the field of immunotherapy. The present invention provides antibodies targeting human SIRPα that enhance cross-presentation of antigens to T cells, useful in therapeutic and diagnostic applications. The present invention also provides antibodies directed against specific isoforms of SIRPα and capable of disrupting the interaction between these isoforms of SIRPα and human CD47 for use in the treatment or prevention of diseases or in diagnostic applications. The present invention also relates to methods of producing and / or screening anti-human SIRPα antibodies that bind with different affinities to various isoforms of human SIRP members. Background technique [0002] Targeting immune checkpoints of adaptive immunity has shown great therapeutic efficacy against a variety of cancers. Immune checkpoints against myeloid cells such as macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs) and polymorphonuclear ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K14/705A61K39/00
CPCC07K14/70503C07K14/70532C07K16/2803C07K2317/34C07K2317/74C07K2317/76C07K2317/80C07K2317/92A61K2039/505Y02A50/30C07K16/2896A61P35/00C07K2317/565A61K45/06
Inventor N·波里尔V·高铁尔C·马里S·彭加马B·瓦努夫
Owner OSE IMMUNOTHERAPEUTICS
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