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Novel bispecific cd3/cd20 polypeptide complex

A polypeptide complex and bispecific technology, applied in the direction of specific peptides, peptides, drug combinations, etc.

Active Publication Date: 2022-07-08
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These severe side effects limit the clinical application of OKT3

Method used

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  • Novel bispecific cd3/cd20 polypeptide complex
  • Novel bispecific cd3/cd20 polypeptide complex
  • Novel bispecific cd3/cd20 polypeptide complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0498] Material Preparation and Reference Antibodies

[0499] 1. Material preparation

[0500] Information on commercially available materials used in the examples is provided in Table 1.

[0501] Table 1. Commercially Available Materials

[0502]

[0503]

[0504] 2. Generation of Benchmark Antibodies

[0505] Two benchmark antibodies, W327-BMK1 and W327-BMK4, were used as reference antibodies in the examples.

[0506] An anti-human CD20 reference antibody BMK1 (rituximab) was generated based on the sequence of clone C2B8 from US patent application US 20140004037A1. The anti-CD3×CD20 reference bispecific antibody BMK4 (REGN1979) gene was synthesized according to the sequence in US patent application US 20150266966 A1. BMK antibody was expressed from Expi293 cells and purified by protein A chromatography.

Embodiment 2

[0508] Preparation of Bispecific Antibodies of the Application

[0509] 1. Design and Engineering of Antibodies and TCR Chimeric Proteins

[0510] TCR sequence

[0511] TCR is a heterodimeric protein composed of two chains. About 95% of human T cells have TCRs composed of alpha and beta chains. Considering that more crystal structures are available for beta-chain TRBC1, the TRBC1 sequence was chosen as the main backbone for designing the polypeptide complex ("WuXiBody") disclosed herein. The canonical amino acid sequence of TRBC1 can be found in the Protein DataBank (PDB) structure 4L4T.

[0512] Interchain disulfide bonds in TCR

[0513] Use the TCR crystal structure to guide our WuXiBody design. Unlike native TCRs, which are anchored on the T cell surface membrane, soluble TCR molecules are less stable, although their 3D structures closely resemble antibody Fabs. In fact, the instability of TCR in the dissolved state has been a major obstacle to the elucidation of its ...

Embodiment 3

[0531] In vitro characterization

[0532] 1. Cell Line and Primary Cell Isolation

[0533] The following cell lines grown in complete medium (RPMI1640 supplemented with 10% FBS, 100 U / ml penicillin, 100 μg / ml streptomycin) were used: Jurkat (CD3+ / CD20- cells); Raji, Ramos and NAMALWA (CD20+ / CD3- cells), SU-DHL-1 (CD20- / CD3- cells).

[0534] Human peripheral blood mononuclear cells (PBMCs) were freshly isolated from heparinized venous blood from healthy normal blood donors by Ficoll-Paque PLUS (GE Healthcare-17-1440-03) density centrifugation. Primary human CD8 isolated from fresh human PBMC by EasySep kit (Stemcell-19053) + T cells, and CD4 purified by EasySep (Stemcell-19052) column + T cells.

[0535] 2. Binding of W3278 BsAb to target cells

[0536] Binding of the W3278 BsAb to target cells was determined by flow cytometry. In short, the 1×10 5Individuals / well of target cells (CD3+ / CD20- cells or CD20+ / CD3- cells) were incubated with serial dilutions of W3278 BsA...

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Abstract

The present invention provides a bispecific anti-CD3xCD20 polypeptide complex comprising a first antigen-binding portion and a second antigen-binding portion, a method for producing the bispecific anti-CD3xCD20 polypeptide complex, and using the bispecific anti-CD3xCD20 polypeptide Methods of treating diseases or conditions with complexes, polynucleotides encoding said bispecific anti-CD3xCD20 polypeptide complexes, vectors and host cells containing said polynucleotides, and combinations comprising said bispecific anti-CD3xCD20 polypeptide complexes substances and pharmaceutical compositions.

Description

[0001] priority information [0002] This application claims priority to Chinese invention patent application 201910080405.3, filed on January 28, 2019, and PCT application PCT / CN2019 / 073418, filed January 28, 2019, which are fully incorporated herein by reference. [0003] sequence listing [0004] A sequence listing file in electronic form is also submitted with this application. The complete contents of the Sequence Listing are incorporated by reference in this disclosure. technical field [0005] The present invention generally relates to bispecific anti-CD3xCD20 polypeptide complexes. Background technique [0006] Bispecific antibodies are a new class of therapeutic antibodies. They can bind two different targets or two different epitopes on one target, resulting in an additive or synergistic effect that is superior to that of a single antibody. There have been many attempts at antibody engineering for the design of new bispecific formats (eg DVD-Ig, CrossMab, Bi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/46C12N15/13A61K39/395A61P35/00A61P35/02
CPCC07K16/2809C07K16/2887A61P35/00A61P35/02C07K2317/31C07K2317/51C07K2317/515C07K2317/94C07K2317/92C07K2317/73A61K2039/505
Inventor 陈蕴颖梅芹徐建清王卓智李竞吕鹏
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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