Anti-hvem antibodies and use thereof

An antibody and reagent technology, applied in the field of immunotherapy, which can solve problems such as side effects, suboptimal patient response rate, adverse reactions, etc.

Pending Publication Date: 2022-02-08
4C BIOMED LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the response rate of patients is still not optimal, because usually only 10% to 40% of treated patients benefit, and at the same time patients may suffer side effects after immunotherapy treatment (Post Immunotherapy Treatments Side-Effects)
Furthermore, treatment with these agents may induce resistance through the upregulation of additional immune checkpoints
The combination of anti-PD1 and anti-CTLA-4 therapy in melanoma patients showed a higher response rate (60%) compared with single agents, however this combination therapy was also associated with serious treatment-related adverse effects

Method used

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  • Anti-hvem antibodies and use thereof
  • Anti-hvem antibodies and use thereof
  • Anti-hvem antibodies and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Example 1: Identification of HVEM as an immune blocking target

[0177]A high-throughput genome-wide primary siRNA screen consisting of approximately 8,300 genes was run on 2 patient-derived melanoma cell systems. Killing was assessed using an LDH-based cytotoxicity assay 96 hours after siRNA transfection by overnight co-culture with TILs. Successful knockdown of positive controls was assessed by FACS. Using the same design as the primary screen—in which positive hits were defined based on their Z-score and percent killing enhancement—a confirmatory screen consisting of 360 genes was validated on eight melanoma cell systems, Correction was made for the effect of siRNA on proliferation. Finally, a validation screen consisting of 54 genes was performed on 5 melanoma cell systems. HVEM was found to have strong positive hits as a potential immunotherapy target.

Embodiment 2

[0178] Example 2: Selection of scFv for HVEM

[0179] Having established HVEM as a potential target for therapeutic immune blockade in cancer therapy, single-chain antibody fragments (scFv) that can bind to HVEM were isolated and assayed. scFvs were isolated as described above (Materials and Methods). Six selected scFvs were screened for binding to recombinant human, mouse and cynomolgus HVEM (see Table 1). Five of the six showed strong binding to human recombinant HVEM (hrHVEM) expressed in CHO-K1 cells as measured by cellular ELISA. CHO-K1-null cells were used as a negative control. Two of these five showed very strong binding to mouse recombinant HVEM (mrHVEM), while the other three showed much weaker binding. One of the five also showed strong binding to monkey (cynomolgus) HVEM, while three of the others showed much weaker binding. FACS analysis was used to confirm these results. The scFv contained a HIS tag and an anti-HIS second APC-conjugated antibody was used to ...

Embodiment 3

[0183] Example 3: Anti-HVEM IgG Antibodies

[0184] Although the single chain antibody scFv2 was effective at blocking the HVEM-BTLA interaction, a fully IgG monoclonal antibody (mAb) was designed from the scFv2 light and heavy chains, specifically the CDRs. The scFv2 was sequenced and the light and heavy chains were cloned into an IgG4 backbone (excluding the S228P mutation). The complete sequence of this mAb heavy chain is present in SEQ ID NO:9 and the light chain is present in SEQ ID NO:10. The presence of intact IgG antibodies was confirmed by SDS-PAGE and Western blotting ( image 3 ).

[0185] Next, the binding of the new mAbs to recombinant HVEM from humans, mice and monkeys was assessed as before. Binding to hrHVEM was assessed by ELISA as before. The new mAbs strongly bind hrHVEM ( Figure 4A ). Binding was also assessed by FACS as before. CHO-K1 empty, CHO-K1 hrHVEM, CHO-K1 mrHVEM, and CHO-K1 crHVEM cells were incubated with 20 μg / ml antibody or hIgG4 isotype...

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Abstract

Agents that bind HVEM, inhibit HVEM-BTLA interaction and activate downstream HVEM signaling are provided. Methods of treating disease with those agents and kits comprising those agents are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 965,921, filed January 26, 2020, and U.S. Provisional Patent Application No. 62 / 839,841, filed April 29, 2019, the contents of which are incorporated by reference in their entirety Incorporated into this article. technical field [0003] The present invention belongs to the field of immunotherapy. Background technique [0004] Immunotherapies designed to boost the immune response are considered activating immunotherapies and are at the forefront of cancer treatment. Currently, immune checkpoint blockade therapy is successfully used in the treatment of advanced non-small cell lung cancer (NSCLC), metastatic melanoma, and advanced renal cell carcinoma (RCC). Some of these drugs are developed and produced by different companies – including targeting the immune checkpoints programmed cell death protein 1 receptor (PD1), programm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61P35/00A61P31/00G01N33/53G01N33/574A61K39/395C07K16/30
CPCA61P35/00A61P31/00G01N2333/70578G01N2800/52G01N33/6872G01N33/57492C07K16/2878A61K2039/505A61K2039/507C07K16/2818C07K2317/73C07K2317/76C07K2317/74C07K2317/622C07K16/3053C07K16/30C07K2317/33C07K2317/52A61K39/3955A61K45/06C07K2317/565
Inventor E·格林伯格G·伽罗雷-哈斯克尔E·梅哈维-肖厄姆G·马尔克尔J·沙赫特
Owner 4C BIOMED LTD
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