Phase I Trial of the Prostate-Specific Membrane Antigen-Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer
ABSTRACT MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704.
Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed.
Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2).
Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.
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ABSTRACT: In the past two decades, monoclonal antibodies have become one of the important therapeutic modalities for the treatment of cancer. Antibody engineering has immensely contributed to the development of anti-body-based cancer therapy. The use of recombinant DNA technology has aided the molecular engineering of antibodies in various ways to improve their effi-cacy, and to counter various challenges posed in the rational designing of high-impact therapeutics for the treatment of a wide spectrum of malignancies. Such engineering of antibodies has been possible mainly due to their inherent plastic and multidomain struc-ture, which makes it amenable to various modifica-tions. This review highlights the advances in the field of antibody engineering which have enabled the use of antibodies for cancer immunotherapy. THE discovery of hybridoma technology by Kohler and Milstein 1 paved the way for the production of monoclonal antibodies against a single antigen. Antibodies are gamma globulin proteins which are used by the immune system to identify and neutralize antigens. Antibodies recognize a particular antigen by virtue of their unique specificity, and tag the antigen for attack by other com-ponents of the immune system. Recognition of the anti-gen follows a series of reactions which destroy the antigen or the infected cell that presents the antigen. Antibodies achieve their toxic effects through antibody-dependent cell-mediated cytotoxicity 2 (ADCC) and com-plement-dependent cytotoxicity 3 (CDC). In ADCC, the antibody first binds to its target antigen present on the surface of tumour cells and the Fc portion is then recog-nized by Fc receptors present on the effector cells such as monocytes, macrophages and natural killer cells. Natural killer cells are the principal effectors of ADCC. ADCC is mediated by the release of cytotoxic granules such as per-forin, granzyme, granulysin, etc., which form pores in the infected cells and cause apoptosis. Additionally, the release of cytokines and chemokines inhibits cell prolifera-tion and angiogenesis. Macrophages bearing Fc receptors on their surface bind and phagocytose antibody-coated tumour cells and promote ADCC through the release of proteases, reactive oxygen species and cytokines 4 . The outcome of the ADCC depends upon the isotype of the antibody; IgGs 1 and 3 bind strongly to the Fc receptor, whereas IgGs 4 and 2 display weak binding 5 . CDC is characterized by the activation of the complement path-way, also known as the complement cascade. The series of reactions in this cascade leads to the formation of a membrane attack complex which forms pores in the cell leading to cell death. CDC also depends upon the isotype of the IgG. IgG3 followed by IgG1 are the most effective isotypes for stimulating the classic complement cascade. IgG2 antibodies are less efficient in activating the com-plement cascade, whereas IgG4 is unable to do so 6 . Antibodies used in immunotherapy mainly exert their activity by blocking ligand–receptor interactions and thereby triggering an intracellular signal which may lead to cell death. Alternatively, binding of an antibody to a target may block a signalling event crucial for metastasis. The recombinant DNA technology has facilitated the engineering of antibodies in a variety of ways. These include engineering to modify their serum persistence, effector mechanisms, introducing new effector functions, humanization and altering size. We discuss, in this review, the various antibody engineering methodologies along with their applications.
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