A Phase 1, Open-label, Dose Escalation Study of the Humanized Monoclonal Antibody, TRC093, in Patients With Locally Advanced or Metastatic Solid Tumors

This study is being performed to evaluate the safety and tolerability of the TRC093 antibody.

开始日期2007-06-01

申办/合作机构

TRACON Pharmaceuticals, Inc.

100 项与 TRC-093 相关的临床结果

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100 项与 TRC-093 相关的转化医学

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100 项与 TRC-093 相关的专利（医药）

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项与 TRC-093 相关的文献（医药）

2024-10-02·SAR AND QSAR IN ENVIRONMENTAL RESEARCH

Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning

Article

作者: Cong, J. ; Zhang, W. ; Du, J. ; Si, X. ; Xu, G. ; Wei, B.

BACE1 has been regarded as an essential drug design target for treating Alzheimer's disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and molecular mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the molecular mechanism underlying the effect of D93 and D289 protonation on binding of inhibitors OV6 and 4B2 to BACE1. The GaMD trajectory-based DL successfully identifies significant function domains. Dynamic analysis shows that the protonation of D93 and D289 strongly affects the structural flexibility and dynamic behaviour of BACE1. Free energy landscapes indicate that inhibitor-bound BACE1s have more conformational states in the protonated states than the wild-type (WT) BACE1, and show more binding poses of inhibitors. Binding affinities calculated using the MM-GBSA method indicate that the protonation of D93 and D289 highly disturbs the binding ability of inhibitors to BACE1. In addition, the protonation of two residues significantly affects the hydrogen bonding interactions (HBIs) of OV6 and 4B2 with BACE1, altering their binding activity to BACE1. The binding hot spots of BACE1 recognized by residue-based free energy estimations provide rational targeting sites for drug design towards BACE1. This study is anticipated to provide theoretical aids for drug development towards treatment of AD.

2007-07-01·Molecular immunology3区 · 医学

Targeting of humanized antibody D93 to sites of angiogenesis and tumor growth by binding to multiple epitopes on denatured collagens

3区 · 医学

Article

作者: Nickel, Jeff ; Baeuerle, Patrick A. ; Freimark, Bruce ; Van Epps, Dennis ; Clark, Derek ; Pernasetti, Flavia ; Myszka, David

A humanized, affinity-matured IgG1 antibody, called D93, and its parental murine IgM HUI77 have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models. In this study, we have identified epitopes for both HUI77 and D93 on human collagen type IV. Several tryptic D93-binding peptides were identified by Western blot analysis and protein sequencing. Epitopes for D93 were ultimately identified by screening a synthetic 16-mer peptide array spanning immunoreactive tryptic peptides. D93 reacted with a peptide corresponding to alpha1(IV) P(1337)-Y(1352) that could inhibit binding of both D93 and HUI77 to denatured collagen IV in a concentration-dependent manner. A 9-mer peptide corresponding to alpha1(IV) G(1344)-Y(1352) showed maximum inhibition of D93 and HUI77 antibody binding to denatured collagen IV, and was critically dependent on the presence of hydroxyproline. D93 bound with similar affinity to denatured collagen IV and synthetic peptides with a K(D) of 1-10 microM for monovalent and of 30-63 nM for bivalent binding. Potential epitopes for D93 are highly repeated in multiple collagen types of diverse vertebrate species explaining reactivity of D93 with denatured collagens types I-V from chicken to man. Our data suggest that D93 inhibits angiogenesis and tumor growth by blockade of cryptic bioactive signals on proteolyzed collagens with importance for growth of tumors and new blood vessels.

2005-11-01·Journal of clinical oncology : official journal of the American Society of Clinical Oncology1区 · 医学

Tamoxifen Versus Control After Adjuvant, Risk-Adapted Chemotherapy in Postmenopausal, Receptor-Negative Patients With Breast Cancer: A Randomized Trial (GABG-IV D-93)—The German Adjuvant Breast Cancer Group

1区 · 医学

Article

作者: Kaufmann, Manfred ; Jonat, Walter ; Geberth, Matthias ; Albert, Ute-Susann ; Graf, Erika ; Conrad, Bettina ; Gademann, Günther ; Stahl, Karin ; von Minckwitz, Gunter ; Eiermann, Wolfgang ; Schumacher, Martin

Purpose:

To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor–negative breast cancer.

Methods:

Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m2, methotrexate, 40 mg/m2, and fluorouracil, 600 mg/m2) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 followed by three cycles of CMF in patients with four to nine positive lymph nodes.

Results:

Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years’ median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients.

Conclusion:

This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.

项与 TRC-093 相关的新闻（医药）

2007-08-30

·BioSpace

Micromet to Present at the Sal. Oppenheim 2nd European Healthcare Conference

BETHESDA, Md., Aug. 30 /PRNewswire-FirstCall/ -- Micromet, Inc. , a biopharmaceutical company focusing on the development of novel, proprietary antibody-based products for cancer, inflammation and autoimmune diseases, today announced that Dr. Christian Itin, President and Chief Executive Officer of Micromet, will present at the Sal. Oppenheim 2nd European Healthcare Conference in Frankfurt, Germany on Wednesday, September 5, 2007 at 9:50am Eastern time (3:50pm central European time). About Micromet, Inc. ( ) Micromet, Inc. is a biopharmaceutical company focusing on the development of novel, proprietary antibody-based products for cancer, inflammation and autoimmune diseases. Three product candidates are currently in clinical trials. MT103, also known as MEDI-538, is the first product candidate based on Micromet's novel BiTE(R) antibody product development platform and is being evaluated in a phase 1 clinical trial for the treatment of patients with non- Hodgkin's lymphoma. The BiTE antibody product development platform is based on a unique, antibody-based class of drugs that leverages the cytotoxic potential of T cells in the treatment of cancer. T cells are the most powerful 'killer cells' of the human immune system. Micromet has established a collaboration with MedImmune, Inc. for MT103/MEDI-538. The second clinical stage product candidate is adecatumumab, also known as MT201, a recombinant human monoclonal antibody which targets EpCAM expressing tumors. Adecatumumab is being developed for the treatment of patients with breast cancer. A phase 2a clinical trial in this indication has been completed and a phase 1b trial evaluating the safety and tolerability of MT201 in combination with docetaxel is currently ongoing in patients with metastatic breast cancer. Our third clinical stage product candidate is D93, also known as TRC093, a first-in- class humanized monoclonal antibody that inhibits angiogenesis and tumor cell growth by binding cleaved collagen. This product candidate is in phase 1 clinical trials and is being developed by TRACON Pharmaceuticals for the treatment of patients with cancer and age-related macular degeneration pursuant to license agreement under which Micromet has granted TRACON the worldwide rights to develop and commercialize D93/TRC093. In addition, Micromet has established a collaboration with Nycomed for the development and commercialization of MT203, Micromet's human antibody neutralizing the activity of granulocyte/macrophage colony stimulating factor (GM-CSF), which has potential applications in the treatment of inflammatory diseases, such as rheumatoid arthritis, as well as autoimmune diseases. Micromet, Inc. CONTACT: Christopher Schnittker, SVP & CFO, Micromet, Inc.,+1-240-752-1421, cschnittker@micromet-inc.com, Investors, Susan Noonan,+1-212-966-3650, susan@sanoonan.com, Patricia Garrison, +1-917-322-2567,pgarrison@rxir.com Web site:

合作抗体

100 项与 TRC-093 相关的药物交易

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