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VARIABLE REGIONS FOR NKp46 BINDING PROTEINS

A variable region and variable technology, applied in the field of variable regions of NKp46 binding proteins, can solve problems such as NK cell-specific bispecific antibodies that have not yet been developed

Active Publication Date: 2018-11-09
INNATE PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] To date, no NK cell-specific bispecific antibodies have been developed

Method used

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  • VARIABLE REGIONS FOR NKp46 BINDING PROTEINS
  • VARIABLE REGIONS FOR NKp46 BINDING PROTEINS
  • VARIABLE REGIONS FOR NKp46 BINDING PROTEINS

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0222] Generation of anti-huNKp46 antibodies

[0223] Part A: Generation of anti-huNKp46 antibodies

[0224] Balb / c mice were immunized with recombinant human NKp46 extracellular domain recombinant Fc protein. Mice received a primary immunization (intraperitoneal injection) with an emulsion of 50 μg NKp46 protein and complete Freund's adjuvant, and a second immunization (intraperitoneal injection) with an emulsion of 50 μg NKp46 protein and incomplete Freund's adjuvant , and finally a boost (iv) with 10 μg of NKp46 protein. Immune splenocytes were fused with X63.Ag8.653 immortalized B cells 3 days after boost and cultured in the presence of irradiated splenocytes.

[0225] Primary screening: Supernatants (SN) of growing clones were tested in primary screening by flow cytometry using cell lines expressing human NKp46 constructs on the cell surface. Briefly, for FACS screening, the presence of reactive antibody in the supernatant was revealed by using PE-labeled goat anti-mou...

example 2

[0302] Identification of bispecific antibody formats that bind FcRn but not FcγR for targeting effector cell receptors

[0303] The purpose of this experiment was to develop a new bispecific protein format that places an Fc domain on a polypeptide together with an anti-NKp46 binding domain and an anti-target antigen binding domain. The bispecific protein binds monovalently to NKp46 through its anti-NKp46 binding domain. The monomeric Fc domain retains at least partial binding to the human neonatal Fc receptor (FcRn), but does not substantially bind to human CD16 and / or other human Fcγ receptors. Thus, bispecific proteins do not induce Fc[gamma]-mediated (eg CD16-mediated) target cell lysis.

Embodiment 2-1

[0304] Example 2-1 Construction and binding analysis of anti-CD19-IgG1-Fcmono-anti-CD3

[0305] Since anti-NKp46 bispecific antibodies that could indicate whether this protein is functional have not been produced, CD3 was used instead of NKp46 as a model antigen to study the function of new monovalent bispecific proteins before targeting NK cells by NKp46.

[0306] A bispecific Fc based on a scFv specific for the tumor antigen CD19 (anti-CD19 scFv) and an scFv specific for the activating receptor CD3 on T cells (anti-CD3 scFv) was used to assess the binding and binding of novel monomeric bispecific polypeptides to FcRn and CD19 binding function. The domain arrangement of the final polypeptide is referred to as the "F1" format (the asterisk in the CH2 domain indicates the optional N297S mutation, not included in the polypeptides tested here).

[0307] Fc-containing bispecific monomeric polypeptides were constructed based on a scFv specific for the tumor antigen CD19 (anti-CD19...

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Abstract

NKp46-binding immunoglobulin variable regions, and proteins such as antibodies and multispecific proteins that comprise the variable regions are provided. The proteins can bind and specifically redirect NK cells to lyse a target cell of interest. The proteins have utility in the treatment of disease, notably cancer or infectious disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Application No. 62 / 271,474, filed on December 28, 2015, which is incorporated herein by reference in its entirety; including any drawings and Sequence Listing. [0003] Sequence Listing Reference [0004] This application is being filed together with a Sequence Listing in electronic format. The sequence listing is provided as a file entitled "NKp46-7PCT_ST25txt", which was created on December 19, 2016 and is 376KB in size. The information in the Sequence Listing in electronic format is incorporated herein by reference in its entirety. technical field [0005] Immunoglobulin variable regions are provided, as well as proteins such as antibodies and multispecific proteins comprising these variable regions. These proteins can bind and specifically redirect NK cells to lyse target cells. These proteins have utility in the treatment of diseases, especially cancer or infe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/18C07K16/46
CPCC07K16/2809C07K16/2887C07K16/468C07K2317/24C07K2317/31C07K2317/33C07K2317/34C07K2317/526C07K2317/622C07K2317/732C07K2317/92C07K16/2803A61P29/00A61P35/00A61P37/04A61P37/06A61P43/00C12N15/66C12N15/64C12N2511/00C12N5/10C12N15/00C12N2523/00
Inventor 劳伦特·戈捷纳迪娅·安塞里斯阿丽亚娜·莫雷尔本杰明·罗西
Owner INNATE PHARMA SA
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