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Platform for constructing multispecific antibody

A multi-specific antibody, antibody technology, applied in the field of building multi-specific antibody platform, can solve the problem of increasing the complexity of dual-targeting concept

Pending Publication Date: 2021-10-01
BIOTHEUS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the increased complexity of the dual-target concept compared to monoclonal antibodies poses additional challenges at different stages of discovery and development, bispecific antibodies present exciting opportunities for the design and development of novel drugs

Method used

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  • Platform for constructing multispecific antibody
  • Platform for constructing multispecific antibody
  • Platform for constructing multispecific antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Example 1: Anti-PD-1 / TIGIT / human serum albumin trispecific antibody

[0218] 1.1 Construction of anti-PD-1 / TIGIT / human serum albumin trispecific antibody

[0219] In order to confirm the M-Body technology, in this example, two anti-PD-1 / TIGIT / human serum albumin trispecific antibodies were constructed:

[0220] Bi-70-71 is composed of 2 polypeptide chains, its structure is as follows figure 1 As shown in A. Peptide chain #1 has the amino acid sequence shown in SEQ ID NO: 1, which includes the VH amino acid sequence (SEQ ID NO: 2) derived from the anti-PD-1 antibody Pembrolizumab (Patent No.: US8354509), the VH amino acid sequence C The terminal is directly connected to the CH1 amino acid sequence (SEQ ID NO: 3) derived from human IgG1. The C-terminus of Nanobody ALB8 (patent number: WO2004 / 041865) with SEQ ID NO: 5 anti-human serum albumin is connected to the Pembrolizumab through a flexible peptide of 11 amino acid residues (GGGGSGGGGSG) (SEQ ID NO: 4). N-terminal ...

Embodiment 2

[0245] Example 2: Anti-VEGF / PD-L1 / human serum albumin trispecific antibody

[0246] 2.1. Construction of anti-VEGF / PD-L1 / human serum albumin trispecific antibody

[0247]In order to confirm whether the M-body is applicable when the connected VH-VL domain is targeting free antigens in blood, in this example, an anti-VEGF / PD-L1 / human serum albumin trispecific antibody was constructed , named Bi-74-76, and its structure diagram is shown in figure 1 As shown in C, it consists of 2 polypeptide chains. Peptide chain #1 has the amino acid sequence shown in SEQ ID NO: 12, which includes the VH amino acid sequence (SEQ ID NO: 13), the C-terminal of the VH amino acid sequence is directly connected to the CH1 amino acid sequence (SEQ ID NO: 3) derived from human IgG1; the C-terminal of the nanobody ALB8 (SEQ ID NO: 5) against human serum albumin is passed A flexible peptide of 11 amino acid residues (GGGGSGGGGSG) (SEQ ID NO: 4) is connected to the N-terminal of the variable region of t...

Embodiment 3

[0262] Example 3: Anti-PD-L1 / PD-L2 / human serum albumin trispecific antibody or anti-PD-L1 / PD-L2 / TIGIT / human serum albumin tetraspecific antibody

[0263] 3.1 Construction of anti-PD-L1 / PD-L2 / human serum albumin trispecific antibody or anti-PD-L1 / PD-L2 / TIGIT / human serum albumin tetraspecific antibody

[0264] In order to verify whether the M-body is applicable when two Nanobodies targeting different targets located in the same cell are connected, the inventors constructed a set of anti-PD-L1 / PD-L2 / human serum albumin trispecific Antibody or anti-PD-L1 / PD-L2 / TIGIT / human serum albumin tetraspecific antibody.

[0265] In this example, three anti-PD-L1 / PD-L2 / human serum albumin trispecific antibodies were constructed:

[0266] Bi-78-79, the schematic diagram of its structure is shown in Figure 11 As shown in A, it consists of 2 polypeptide chains. Peptide chain #1 has the amino acid sequence shown in SEQ ID NO: 17, which contains the anti-PD-L1 Nanobody C-Ye-18-5 (SEQ ID NO: 14)...

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Abstract

The invention provides a platform for constructing a multispecific antibody. Specifically, the invention provides a method for constructing a multispecific antibody, which comprises the following steps: (i) respectively constructing a first polynucleotide and a second polynucleotide which respectively encode a first polypeptide containing a CL region and a second polypeptide containing a CH1 region, a disulfide bond can be formed between the CL region of the first polypeptide and the CH1 region of the second polypeptide, so that the antibody has a heterodimer form; and (ii) expressing the first polynucleotide and the second polynucleotide so as to obtain the first polypeptide and the second polypeptide, and dimerizing the first polypeptide and the second polypeptide so as to form the multispecific antibody in a heterodimer form. The antibody can be combined with different target spots at the same time and maintain the binding activity of the original antibody, is effective when the target spot is a membrane surface receptor or a target spot in a solution, and remarkably has the biological activity of resisting multiple target spots.

Description

technical field [0001] The invention belongs to the technical field of biomedicine or biopharmaceuticals, and specifically relates to a platform for constructing multispecific antibodies. Background technique [0002] In 1960, Nisonoff and his collaborators at Roswell Park Memorial Institute in New York first proposed the original concept of bispecific antibodies. Afterwards, with the milestone progress in the fields of antibody engineering and antibody biology, the concept and technology of constructing bispecific antibodies continued to innovate. There are currently more than 100 structural models of bispecific antibodies, of which about a quarter have been developed into technology platforms and commercialized by biotech and pharmaceutical companies for novel antibody therapeutics. Up to now, more than 20 different commercialized technology platforms are available for the development of bispecific antibodies, and more than 85 bispecific antibodies are in the clinical dev...

Claims

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Application Information

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IPC IPC(8): C07K16/46C12N15/13C07K19/00A61K39/395A61K47/68A61P35/00A61P35/02
CPCC07K16/2818C07K16/2827C07K16/18A61K47/6879A61P35/00A61P35/02A61K2039/505C07K2319/30C07K2317/31C12N2511/00C07K16/2803C07K2317/76C07K16/2878C07K16/22C07K2317/569C07K2317/22C07K2317/64C07K2317/92C07K16/00C07K2317/73C07K16/468C07K2317/52C12N15/63
Inventor 刘晓林曾竣玮孙左宇缪小牛王涛戴爽
Owner BIOTHEUS INC
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