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Anti-PD-1-anti-VEGFA bispecific antibodies, pharmaceutical compositions and uses thereof

A bispecific antibody, PD-1 technology, applied in the field of tumor therapy and immunology biology, can solve the problems of poor prognosis, unrealizable metastasis, and high late metastasis rate

Pending Publication Date: 2021-05-25
AKESO BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The treatment effect of malignant tumors is poor, the late metastasis rate is high, and the prognosis is often poor
Although conventional treatment methods such as radiotherapy, chemotherapy and surgery are currently used clinically, although the pain is relieved to a large extent and the survival time is prolonged, these methods have great limitations, and the curative effect is difficult to further improve.
[0003] The growth of tumor has two distinct stages, that is, from the slow growth period without blood vessels to the rapid proliferation period with blood vessels. The formation of blood vessels enables the tumor to obtain enough nutrition to complete the vascular switching period. If there is no angiogenesis, The growth of the primary tumor does not exceed 1-2mm, and the metastasis cannot be achieved

Method used

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  • Anti-PD-1-anti-VEGFA bispecific antibodies, pharmaceutical compositions and uses thereof
  • Anti-PD-1-anti-VEGFA bispecific antibodies, pharmaceutical compositions and uses thereof
  • Anti-PD-1-anti-VEGFA bispecific antibodies, pharmaceutical compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0327] Preparation Example 1: Preparation of Anti-VEGFA Antibody Bevacizumab

[0328] For the amino acid sequences of the heavy chain variable region and the light chain variable region of the marketed anti-VEGFA monoclonal antibody Avastin (Bevacizumab), refer to Chinese patent publication CN1259962A. The nucleic acid sequences encoding the variable region of the heavy chain and the variable region of the light chain were synthesized by GenScript.

[0329] Amino acid sequence of Bevacizumab heavy chain variable region (Bevacizumab-Hv): (123aa)

[0330] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS (SEQ ID NO: 1)

[0331] Nucleic acid sequence encoding Bevacizumab heavy chain variable region: (369bp)

[0332] GAGGTGCAGCTGGTCGAGTCCGGGGGGGGGCTGGTGCAGCCAGGCGGGTCTCTGAGGCTGAGTTGCGCCGCTTCAGGGTACACCTTCACAAACTATGGAATGAATTGGGTGCGCCAGGCACCAGGAAAGGGACTGGAGTGGGTCGGCTGGATCAACACTTACACCGGGGAACCTACCTATGCAGCCGACTTT...

preparation example 2

[0340] Preparation Example 2: Anti-PD-1 antibody 14C12, its humanized antibody 14C12H1L1 and mutant 14C12H1L1(M) sequence design

[0341] The amino acid sequences of the heavy and light chains of the anti-PD-1 antibody 14C12 and its humanized antibody 14C12H1L1, as well as the coding nucleic acid sequences are the same as those of 14C12 and 14C12H1L1 in Chinese Patent Publication CN 106967172A.

[0342] (1) Heavy chain variable region sequence and light chain variable region sequence of 14C12

[0343] Amino acid sequence of the heavy chain variable region of 14C12: (118aa)

[0344] EVKLVESGGGLVKPGGSLKLSCAASGFAFSSYDMSWVRQTPEKRLEWVATISGGGRYTYYPDSVKGRFTISRDNARNNTLYLQMSSLRSEDTALYYCANRYGEAWFAYWGQGTLVTVSA (SEQ ID NO: 5)

[0345] Nucleic acid sequence encoding the heavy chain variable region of 14C12: (354bp)

[0346] GAGGTCAAACTGGTGGAGAGCGGCGGCGGGCTGGTGAAGCCCGGCGGGTCACTGAAACTGAGCTGCGCCGCTTCCGGCTTCGCCTTTAGCTCCTACGACATGTCATGGGTGAGGCAGACCCCTGAGAAGCGCCTGGAATGGGTCGCTACTATCAGCGGAGGC...

preparation example 3

[0374] Preparation Example 3: Sequence Design of Bispecific Antibody

[0375] 1. Sequence Design

[0376] The structural mode of the bispecific antibody in the present invention belongs to the Morrison mode (IgG-scFv), that is, the C-terminus of the two heavy chains of an IgG antibody is connected to the scFv fragment of another antibody, and the main components of the heavy chain and the light chain are The compositional design is shown in Table 1 below.

[0377] On the basis of the above-mentioned Bevacizumab, the VP101 antibody with the amino acid sequences of the heavy chain variable region and light chain variable region of the above-mentioned 14C12H1L1(M) as the ScFv fragment is called VP101(M). Compared with 14C12H1L1, 14C12H1L1(M) effectively optimizes the structure of the bispecific antibody and improves its effectiveness.

[0378] Table 1: Compositional design of the heavy and light chains of VP101(M) and VP101(G4M)

[0379]

[0380]

[0381] In Table 1 ab...

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Abstract

The invention belongs to the field of tumor treatment and molecular immunology, and relates to an anti-VEGFA-anti-PD-1 bispecific antibody and an application thereof. Specifically, the anti-VEGFA-anti-PD-1 bispecific antibody comprises a PD-1-targeting first protein functional region and a VEGFA-targeting second protein functional region, according to an EU numbering system, a heavy chain constant region of immune globulin contained in the bispecific antibody mutates at two sites of 234 and 235, and after mutation, the affinity constant of the bispecific antibody is reduced compared to the affinity constant of Fc [gamma] RI, Fc [gamma] RIIa, Fc [gamma] RIIIa and / or C1q before mutation. The bispecific antibody disclosed by the invention can be specifically combined with VEGFA and PD-1, specifically relieve immunosuppression of VEGFA and PD-1 on an organism and inhibit angiogenesis caused by tumors at the same time, and has a good application prospect.

Description

technical field [0001] The invention belongs to the fields of tumor treatment and immunology biology, and relates to an anti-PD-1-anti-VEGFA bispecific antibody, its drug combination and its application. Specifically, the present invention relates to an anti-human PD-1-anti-human VEGFA bispecific antibody, its pharmaceutical combination and its use. Background technique [0002] Tumors, especially malignant tumors, are diseases that seriously endanger human health in the world today, ranking second among the deaths caused by various diseases. And in recent years, its incidence has shown an obvious upward trend. The curative effect of malignant tumors is poor, the rate of advanced metastasis is high, and the prognosis is often poor. Although conventional treatment methods such as radiotherapy, chemotherapy and surgery are currently used clinically, although the pain is relieved to a large extent and the survival time is prolonged, these methods have great limitations, and t...

Claims

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Application Information

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IPC IPC(8): C07K16/46G01N33/68G01N33/574A61K39/395A61P35/00A61P35/02
CPCC07K16/2818C07K16/22G01N33/68G01N33/74G01N33/574G01N33/57492G01N33/57484A61P35/00A61P35/02C07K2317/31C07K2317/622C07K2317/565C07K2317/56C07K2317/52C07K2317/51C07K2317/515C07K2317/92C07K2317/76C07K2317/77G01N2333/70521G01N2333/475G01N33/57407G01N2333/70532G01N2800/7014C07K2317/24C07K2317/524C07K2317/732C07K2317/734A61K39/395C07K16/00C07K16/46G01N2333/70503A61K2039/505A61K47/6845A61K47/6849
Inventor 张鹏李百勇夏瑜王忠民
Owner AKESO BIOPHARMA
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