Phase 1 long term data of tirelizumab and the results of its structure and mechanism analysis

April 2, 2019 / AP / -- Baiji Shenzhou (NASDAQ Code: bgne; Hong Kong stock exchange code: 06160) is a biomedical company in the commercial stage, focusing on the development and commercialization of innovative molecular targeting and immunotumor drugs for cancer treatment On April 1, the company published the phase 1 long-term research data of its anti PD-1 antibody tirelizumab and the analysis of its structure and binding mechanism in the form of posters at the annual meeting of American Association for cancer research (AACR) The conference will be held in Atlanta, Georgia from March 29 to April 3, 2019 "We believe that the results of these two studies provide further support for a wide range of clinical research projects of tirelizumab as a potential differential anti-PD-1 antibody The long-term data of single drug treatment showed that tirelizumab was well tolerated in general when administered for more than 12 months, and had a long-lasting antitumor effect in multiple cancer patients regardless of the expression of PD-L1 Another non clinical study, published in poster form, for the first time identified the key sites that distinguish tirelizumab from the approved anti-PD-1 antibody in molecular binding mechanism " Poster data (poster No.: ct084, panel 8) for a long term study (LTE) phase 1 clinical study of a phase 1 clinical study of tirelizumab, an anti PD-1 antibody under development This multicenter, open-ended tirelizumab phase 1 clinical study (clinical trials Gov registration number: nct02407990) is being carried out in Australia, New Zealand, the United States, Taiwan and South Korea as a single drug for the treatment of advanced solid tumor patients The research direction includes dose increase, program extension, fixed dose extension, and indication extension The first human trial (FIH) has now enrolled more than 450 patients As of October 27, 2018, 65 patients were treated with tirelizumab for more than 12 months and included in LTE analysis The 65 patients were divided into two groups: dose increasing group and dose expanding group Most patients (n = 46) received 5 mg / kg tirelizumab once every three weeks, the others received 2 mg / kg, once every three weeks (n = 9), the dose was 2 mg / kg, once every two weeks (n = 2), the dose was 5 mg / kg, once every two weeks (n = 5), the dose was 200 mg, once every three weeks (n = 3) The most common cancers (defined as no less than five LTE patients) in this LTE study were non-small cell lung cancer (NSCLC; n = 9), liver cell cancer (HCC; n = 8), bladder cancer (n = 5), and ovarian cancer (n = 5) At a median follow-up of 27.2 months, the objective response rate (ORR) was 68% in LTE patients, and complete response (CR) was achieved in four patients, including squamous cell carcinoma, endometrial carcinoma, bladder carcinoma and esophageal carcinoma (one case for each) PD-L1 was positive in all four patients Partial remission (PR) and disease stability (SD) were observed in both PD-L1 positive and PD-L1 negative tumors The median duration of remission (DOR) in patients with LTE was 21.1 months The overall tolerance of tirelizumab was good after 12 months As of the cut-off point, 52 (80%) of the 65 patients experienced at least one treatment-related adverse event (RAE), mostly mild or moderate Rash is the only Rae reported in more than 15% of patients, with no rash of grade 3 or more reported Trae of grade 3 or above includes arthritis, diarrhea, asthenia, hyperglycemia, elevated alanine aminotransferase, papular rash, and lichen planus keratosis (one case each) Severe Rae occurred in three patients, including fever (n = 2) and arthritis (n = 1), and was relieved Three patients interrupted the study due to adverse events (AE) There was no AE leading to death The molecular binding mechanism of tirelizumab, an anti-PD-1 antibody in research, is different from the poster data before clinical application of paimu mAb and nawumab (poster No.: 2383, panel 7) In this non clinical study, the crystal structure of the complex formed by the extracellular domain of PD-1 and the antigen binding fragment of tirelizumab (FAB) was analyzed to show its molecular binding mechanism, and the binding mechanism of tirelizumab was compared with that of paimummab and nawumab compared with that of PD-1 by structure directed mutation and surface plasmon resonance Three complementary decision regions (CDRs) of light chain variable domain and two CDRs of heavy chain variable domain interact with PD-1 extensively Compared with pamumab and nawumab, the dissociation rate of tirelizumab and wild-type PD-1 slowed down about 100 times and 50 times respectively At the same time, tirelizumab showed different combination directions of PD-1 with pamumab and nawumab The binding surface of PD-1 was overlapped with that of paimu mAb, but it was different from that of nawumab Compared with the two anti-PD-1 antibodies, gln75, thr76, asp77 and Arg86 amino acids in PD-1 were identified as key epitopes in the binding with tirelizumab, but the mutation of these epitopes had little effect on the binding of paimumab and nawumab to PD-1 The results show that the specific binding position, the unique binding epitope and the binding dynamics between tirelizumab and PD-1 are different from those of pamumab and nawumab About tirelizumab tirelizumab (bgb-a317) is a monoclonal antibody against programmed death receptor-1 (PD-1) of human lgg4, which is under research The design purpose is to minimize the binding with Fc receptor in macrophage Preclinical data show that Fc receptor binding in macrophages can activate antibody dependent cell mediated killing of T cells, thus reducing the anti-tumor activity of PD-1 antibody Tirelizumab is the first candidate drug developed by Baiji's immune tumor platform It is currently being developed as a single drug therapy and combination therapy for a series of solid tumor and blood tumor treatment indications Baiji Shenzhou's extensive clinical research projects for tirelizumab include a global phase 3 clinical study for patients with second-line non-small cell lung cancer (NSCLC), a global phase 3 clinical study for patients with first-line liver cancer (HCC), a global phase 3 clinical study for patients with second-line esophageal squamous cell carcinoma (ESCC), and a global phase 3 clinical study for patients with first-line gastric cancer (GC) Our global phase 3 clinical study; a global phase 3 clinical study for first-line ESCC patients; a global phase 3 clinical study for third-line NSCLC patients; a global phase 2 clinical study for second-line to third-line HCC patients; a global phase 1 clinical study for relapsed / refractory (R / R) NK / T cell lymphoblastoma patients; and a global phase 1 clinical study for solid tumor patients Research In China, Baiji Shenzhou has completed a critical phase 2 clinical study for patients with R / R classic Hodgkin's lymphoma (CHL), and is carrying out a phase 3 clinical study for patients with first-line non squamous NSCLC, a phase 3 clinical study for patients with squamous NSCLC, a phase 2 clinical study for patients with second-line urothelial carcinoma (UC), and a phase 2 clinical study for patients with second-line urothelial carcinoma (UC) Phase 2 clinical study of solid tumor patients with high microsatellite instability (MSI-H) or mismatch repair defect (dmmr) The application of tirelizumab for the treatment of R / rchl in China has been accepted by China National Drug Administration (nmpa) and included in the priority review Baiji Shenzhou has entered into a global strategic partnership with Xinji company, authorizing Xinji company to develop tirelizumab for solid tumor treatment in Asia (except Japan) About Baiji Shenzhou, a global, commercial stage, R & D-based biotechnology company, focusing on the research and development of molecular targeting and immunotherapy for tumor At present, Baiji Shenzhou has more than 2200 employees in mainland China, the United States, Australia and Europe, and its research product line includes new oral small molecule and monoclonal antibody anti-cancer drugs At present, Baiji Shenzhou is also building a drug combination program for anti-cancer treatment, aiming to bring lasting and far-reaching impact on the life of cancer patients Under the authorization of Xinji company, Baiji Shenzhou sells Abraxane ® paclitaxel for injection (nano albumin particle binding type), refume ® (lenalidomide) and vedasha ® (azacytidine for injection) [i] in China.