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Anti-cd137 molecules and use thereof

An antibody and antigen technology, applied in the direction of antibody medical ingredients, medical preparations containing active ingredients, antibodies, etc., can solve problems such as unsatisfied and increased CD137 mediation

Pending Publication Date: 2020-08-07
ADAGENE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There is a long-felt unmet need for antibodies that bind human CD137, increase CD137-mediated responses, and thereby provide potential therapeutic agents for the treatment of various diseases and conditions, including cancer and autoimmune diseases

Method used

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  • Anti-cd137 molecules and use thereof
  • Anti-cd137 molecules and use thereof
  • Anti-cd137 molecules and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0194] Generation of primary Fabs that specifically bind human CD137

[0195] Using a proprietary plasmid library (see PCT International Application entitled "Dynamic Human Antibody Light Chain Libraries," filed concurrently under Attorney Docket No. 69540-2000140, which is hereby incorporated by reference in its entirety; see also at Attorney PCT International Application entitled "Dynamic Human Heavy Chain Antibody Libraries" filed concurrently under Docket No. 69540-2000240, which is hereby incorporated by reference in its entirety) pans against human CD137 antigen. A total of three or four rounds of panning were performed. After the final round of panning, a single colony supernatant ELISA was performed to identify primary hits that specifically recognized human CD137. Primary hits were defined as those whose ELISA signal was at least twice background. They were sequenced and unique clones were expressed and purified for affinity measurements by ForteBio and Biacore. Th...

Embodiment 2

[0211] Selection of Fab hits that cross-react with mouse CD137

[0212] Species cross-reactivity of Fab hits was determined using ELISA. Briefly, 200 μL of 5 μg / mL anti-human IgG (Fab specific) (Sigma #I5260) was plated onto Maxisorp microplates (Thermo Scientific 446469) overnight at 4°C. After blocking, 100 μL of Fabs 5310 (5 μg / mL), 5351 (2.8 μg / mL) and 5365 (5 μg / mL) were added and incubated for 1 hr. After three washes, serial dilutions of human or mouse CD137 antigen fused to the human FC fragment were added and incubated for 1 hr. After washing, HRP-labeled goat anti-human FC was diluted 1:2000 with PBS and added to each well and incubated for 1 hr. Plates were washed three times and incubated with TMB substrate for 20 min at room temperature. After the reaction was stopped, the absorbance at 450 nm was measured. The results are presented in Figure Ib, the lower panel shows that Fabs 5310 and 5365 bind both human and mouse CD137, while Fab5351 binds human CD137, but...

Embodiment 3

[0214] IgG conversion and expression: AG10058, AG10059 and AG10131

[0215] The heavy and light chains of Fabs 5310, 5351 and 5365 were cloned individually into the mammalian expression vector pCDNA3.3 (Thermo Fisher Scientific) in the IgG4 isotype with the S241P mutation. The heavy and light chains of the two reference antibodies were additionally cloned into pCDNA3.3 in the IgG4 and IgG2 isotypes, respectively.

[0216] 参考抗体AC1097中使用的重链可变区包含序列EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSS(SEQ ID NO:862),并且参考抗体AC1097中的轻链可变区包含序列SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCATYTGFGSLAVFGGGTKLTVL(SEQ ID NO:863)。 参考抗体AC1121中使用的重链可变区包含序列QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVSS(SEQ ID NO:864),并且参考抗体AC1121中的轻链可变区包含序列EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEP...

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PUM

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Abstract

The present disclosure provides antibodies that bind to human CD137 or antigen binding fragments thereof, nucleic acid encoding the same, therapeutic compositions thereof, and their use to enhance T-cell function to upregulate cell-mediated immune responses and for the treatment of T cell dysfunctional disorders, such as tumor immunity, and for the treatment of cancer.

Description

[0001] References to Sequence Listings [0002] The content of the following submission on the ASCII text file is hereby incorporated by reference in its entirety: Sequence Listing in Computer Readable Form (CRF) (Filename: 695402000340seqlist.txt, Date of Record: August 3, 2017, Size: 537KB). technical field [0003] The present disclosure relates to antibodies or antigen-binding fragments thereof that bind to human CD137, nucleic acids encoding the antibodies or antigen-binding fragments thereof, therapeutic compositions of the antibodies or antigen-binding fragments thereof, and their antitumor uses. Background technique [0004] CD137 (also known as CD137 receptor, 4-1BB, TNFRSF9, etc.) is a transmembrane protein of the tumor necrosis factor receptor superfamily (TNFRS). Current understanding of CD137 suggests that its expression is often activation-dependent and present on a broad subset of immune cells, including activated NK and NKT cells, regulatory T cells, dendriti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/13A61K39/395A61P35/00
CPCC07K16/2878A61K39/39558A61K45/06A61P35/00C07K2317/565C07K2317/56C07K2317/75C07K2317/33C07K2317/92C07K2317/76A61K2039/505A61K39/001102C07K2317/21A61K2039/545A61K39/39591C07K2317/94A61K2039/507C07K16/2818A61K39/3955C07K2317/52C07K2317/55
Inventor 罗培志杜方勇刘桂中李艳陈俊佘晓红P·张
Owner ADAGENE INC
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