calicheamicin-gamma(1)i and Ovarian-Neoplasms

Antibody-targeted chemotherapy is a therapeutic strategy in cancer therapy that involves a monoclonal antibody specific for a tumour-associated antigen, covalently linked via a suitable linker to a potent cytotoxic agent. Tumour-targeted delivery of a cytotoxic agent in the form of an immunoconjugate is expected to improve its antitumour activity and safety. Calicheamicin is a cytotoxic natural product isolated from Micromonospora echinospora that is at least 1000-fold more potent than conventional cytotoxic chemotherapeutics. Calicheamicin binds DNA in the minor groove and causes double-strand DNA breaks, leading to cell death. Immunoconjugates of calicheamicin targeted against tumour-associated antigens exhibit tumour-specific cytotoxic effects and cause regression of established human tumour xenografts in nude mice. Gemtuzumab ozogamicin is the first clinically validated cytotoxic immunoconjugate in which a humanised anti-CD33 antibody is linked to a derivative of calicheamicin. Gemtuzumab ozogamicin is indicated for the treatment of elderly patients with relapsed acute myeloid leukaemia. A similar conjugate, inotuzumab ozogamicin, is being evaluated at present in Phase I clinical trials in patients with non-Hodgkin's lymphoma. A number of tumour-targeted immunoconjugates of calicheamicin are being explored preclinically at present for their therapeutic applications.

Topics: Aged; Aminoglycosides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; DNA Damage; Drug Delivery Systems; Enediynes; Female; Gemtuzumab; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Immunoconjugates; Inotuzumab Ozogamicin; Mice; Mice, Nude; Middle Aged; Neoplasms; Ovarian Neoplasms; Sialic Acid Binding Ig-like Lectin 3; Xenograft Model Antitumor Assays

Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.. A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.. We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification.. These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development.

Topics: Aminoglycosides; Animals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, Neoplasm; Cell Line, Tumor; DNA; Drug Design; Enediynes; Ephrin-A4; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Ovarian Neoplasms; Prospective Studies; Random Allocation; Treatment Outcome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays