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Use of anti-PD-1 antibody in tumor treatment

A technology of PD-1 and PD-L1, which is applied in the direction of anti-tumor drugs, antibody medical components, antibodies, etc., can solve the problems of limited research and poor effect

Inactive Publication Date: 2021-08-13
SHANGHAI JUNSHI BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Retrospective study by Cho, J. et al., Invest New Drugs (2016), 34:677-84 shows that immunotherapy is less effective in ALM and MM compared with CSD melanoma
Therefore, there are uncertainties in the efficacy of immunotherapy, such as anti-PD-1 antibody, in the treatment of melanoma, especially in the treatment of mucosal and acral melanoma, which often occurs in Asian populations, and how to further improve its therapeutic effect is a must. Technical problems urgently needed to be solved in this field
And, although immune checkpoint inhibitor therapy has made major improvements in the treatment of metastatic melanoma over the past decade, most of the skin types in Caucasians (also known as non-acral types) On melanoma, the research on Asian and African races is very limited, resulting in a large gap in the treatment of non-acral and primary melanoma in these two races, which needs to be solved urgently

Method used

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  • Use of anti-PD-1 antibody in tumor treatment
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  • Use of anti-PD-1 antibody in tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1: Clinical research of anti-PD-1 antibody monotherapy in the treatment of melanoma

[0161] Inclusion Criteria: Eligible subjects must be (1) at least 18 years old, (2) have locally advanced or metastatic melanoma, (3) refractory to standard systemic therapy, (4) ECOG score 0 or 1, (5) no history of autoimmune disease or persistent infection, (6) no previous anti-PD-1 / or anti-PD-L1 immunotherapy.

[0162] Subjects must have evaluable lesions according to RECIST v 1.1 standards, and are not allowed to use anti-tumor drug therapy, systemic steroid drug therapy or have not used anti-CTLA4, anti-PD-1, anti-PD-L1 antibody therapy.

[0163] Test drug: anti-PD-1 antibody toripalimab (WO2014206107).

[0164] The dose of anti-PD-1 antibody used in this test is: 3mg / kg, administered intravenously once every two weeks (Q2W).

[0165] Clinical design:

[0166] This is a single-arm, Phase II, open-label clinical trial. This study is to evaluate the safety and anti-tumor...

Embodiment 2

[0194] Example 2: Research on the correlation between biomarkers and clinical efficacy

[0195] 2.1 Expression of PD-L1 in tumors

[0196] The tumor biopsy specimens of 127 patients were tested to analyze the correlation between tumor histology and anti-PD-1 antibody clinical efficacy. The rabbit anti-human PD-L1 antibody SP142 from Roche was used for detection. PD-L1 positive status was defined as the presence of ≥1% membrane staining intensity of tumor cells.

[0197] Such as Image 6 As shown in (A), 26 cases (20.5%) were positive for PD-L1, 84 cases (66.1%) were negative for PD-L1, and the expression of PD-L1 was unknown in 17 cases (13.4%). Such as Image 6 (B) In the four subtypes of melanoma, PD-L1 + The proportion of acral type (6.8%) and mucosal type (10.5%) is significantly lower than that of non-acral type (37.5%) and melanoma of uncertain primary focus (52.2%).

[0198] Such as Image 6 (C) and 6(D), PD-L1 + patients compared to PD-L1 - Patients treated wi...

Embodiment 3

[0205] Example 3: Gene sequencing analysis

[0206] In the experiment of Example 1, whole exome sequencing was performed on tumor biopsies and paired peripheral blood samples from patients using second-generation sequencing technology, and 19,278 gene mutations were identified from 98 patients, including 7964 missense mutations, 509 gene deletions, 482 rearrangements, 288 alternative splicing sites, 129 frameshift truncations and 8157 gene amplifications. After excluding frequently mutated genes in the public exome, the most frequently altered genes (≥10%) were BRAF (33%), TERT (32%), CDKN2A (12%), NRAS (16%) ), CDK4 (12%), APOB (11%), CCND1 (11%), AGAP2 (11%), NF1 (10%), LRP1B (10%), MDM2 (10%) and KIT (10%), see details Figure 7 .

[0207] As shown in Table 6, sequencing results from 98 patients revealed distinct patterns of genomic alterations in melanoma subgroups. BRAF mutations were more frequent in nonacral cutaneous subtypes (11 / 23, 48%) and melanomas of unknown p...

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Abstract

The present invention relates to the use of an anti-PD-1 antibody in the treatment of melanoma. The invention also relates to application of reagents for detecting BRAF, NRAS and CDK4 / CCND1 gene mutations in a detection kit for predicting the treatment effect of a melanoma patient on independently applying the anti-PD-1 antibody and / or the antigen binding fragment thereof.

Description

technical field [0001] The present invention relates to the use of anti-PD-1 antibody in treating tumors. Specifically, the present invention relates to the use of anti-PD-1 antibodies in the treatment of melanoma; and the use of anti-PD-1 antibodies in the preparation of drugs for the treatment of melanoma; and the use of biomarkers to predict the use of anti-PD-1 antibodies alone Efficacy of methods in the treatment of melanoma. Background technique [0002] Immune escape is one of the hallmarks of cancer. Ahmadzadeh, M. et al., Blood, 114:1537-44 disclosed that tumor-specific T lymphocytes often exist in the tumor microenvironment, draining lymph nodes and peripheral blood, but due to the immunosuppressive mechanism network existing in the tumor microenvironment, their Often the progression of the tumor cannot be controlled. CD8 + Tumor-infiltrating T lymphocytes (TILs) often express activation-induced inhibitory receptors, including CTLA-4 and PD-1, while tumor cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/519A61K31/506A61P35/00A61P35/04C12Q1/6886
CPCC07K16/2818A61K39/39558A61K31/519A61K31/506A61P35/00A61P35/04C12Q1/6886C07K2317/565C07K2317/76A61K2039/505C12Q2600/156C12Q2600/106A61K2300/00A61K39/3955A61K2039/545C12Q1/6869
Inventor 姚盛冯辉武海
Owner SHANGHAI JUNSHI BIOSCI
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