maytansine and Hodgkin-Disease

The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody-drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent. The approval of brentuximab vedotin in 2011 for treating relapsed Hodgkin's lymphoma and systemic anaplastic large cell lymphoma, and the approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive metastatic breast cancer, have sparked vigorous research in the field, with >65 ADCs currently in clinical evaluation. This review highlights the ADCs that are approved for marketing, in pivotal clinical trials, or in at least phase II clinical development for treating both hematologic malignancies and solid tumors.

Topics: Ado-Trastuzumab Emtansine; Breast Neoplasms; Brentuximab Vedotin; Drug Development; Hodgkin Disease; Humans; Immunoconjugates; Lymphoma, Large-Cell, Anaplastic; Maytansine; Neoplasms; Trastuzumab

The identification of epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements and the development of targeted therapy for patients with these molecular alterations has been a tremendous advance in the treatment of advanced stage or metastatic non-small cell lung cancer (NSCLC). However, the majority of patients with advanced stage NSCLC will not have one of these molecular alterations and will receive chemotherapy as their primary therapy. Chemotherapy remains a critical component of therapy for resected and locally advanced NSCLC, as well as for patients with limited-stage and extensive stage small cell lung cancer (SCLC). A significant unmet need exists to develop novel chemotherapy agents and to improve the efficacy and toxicity of currently available agents. Several novel formulations of currently available chemotherapy agents are in development for NSCLC and SCLC. Antibody conjugates are therapeutic agents that employ a tumor-specific monoclonal antibody conjugated to a cytotoxic or radionuclide agent. After the monoclonal antibody binds to the tumor antigen, these agents are internalized, and the link between the antibody and the therapeutic agent is dissolved and the cytotoxic agent is release intracellularly. This enhanced delivery of chemotherapy to malignant tissues has the potential to improve efficacy and reduce toxicity. Antibody conjugates to therapeutic agents are currently available for other malignancies and are in development for NSCLC and SCLC.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Hodgkin Disease; Humans; Liposomes; Lung Neoplasms; Lymphoma, Non-Hodgkin; Maytansine; Small Cell Lung Carcinoma

Topics: Ado-Trastuzumab Emtansine; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Brentuximab Vedotin; Female; Gemtuzumab; Hodgkin Disease; Humans; Immunoconjugates; Maytansine; Sialic Acid Binding Ig-like Lectin 3; Trastuzumab

Antibody-drug conjugates (ADCs) combine cytotoxic chemotherapy and antibody specificity. There are 4 components of ADC technology: the cancer, or target, antigen; the antibody to that target; the linker that connects the drug to the antibody; and the drug itself. The antibody directs the cytotoxic agent to the tumor cell, thereby diminishing the side effect profile of the cytotoxic agent and enabling delivery of a more potent therapeutic because of the ability to control the target and the side effects. ADC technology has vastly improved within the last several years. In early ADCs, the linkers were too labile, which led to the release of free drug in the circulation and consequent off-target toxicity. In the current generation of ADCs, the linkers are more stable, and the cytotoxic agents are significantly more potent. ADCs have been developed against a variety of antigens and receptors, including CD19, CD22, and CD30, and have been linked to multiple different cytotoxic agents, including calicheamicin and maytansinoid derivatives. The ADC brentuximab vedotin was recently approved by the US Food and Drug Administration for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or at least 2 prior multiagent chemotherapy regimens, and the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least 1 prior multiagent chemotherapy regimen. Other ADCs in clinical trials for hematologic disorders include inotuzumab ozogamicin, SAR3419, and gemtuzumab ozogamicin.

Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antigens, CD; Antineoplastic Agents; Brentuximab Vedotin; Clinical Trials as Topic; Gemtuzumab; Hodgkin Disease; Humans; Immunoconjugates; Immunotherapy; Inotuzumab Ozogamicin; Lymphoma, Large-Cell, Anaplastic; Maytansine; Morpholines; Recurrence