calicheamicin-gamma(1)i and Lymphoma--B-Cell

Targeted delivery of cytotoxic agents to tumours is believed to improve both their anti-tumour efficacy and their safety. Antibodies specific for tumour-associated antigens have been used to deliver cytotoxic agents to tumour cells. Calicheamicin is a potent cytotoxic agent that causes double-strand DNA breaks, resulting in cell death. When conjugated to monoclonal antibodies specific for tumour-associated antigens, calicheamicin exerts strong antigen-specific anti-tumour effects against human tumour xenografts in preclinical models. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin, exemplified by gemtuzumab ozogamicin (Mylotarg), is a clinically validated therapeutic strategy for the treatment of human cancer.

Topics: Aminoglycosides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Cell Adhesion Molecules; Clinical Trials as Topic; Enediynes; Gemtuzumab; Humans; Immunoconjugates; Inotuzumab Ozogamicin; Lectins; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Sialic Acid Binding Ig-like Lectin 2

Tumor-targeted delivery of a potent cytotoxic agent, calicheamicin, using its immunoconjugates is a clinically validated therapeutic strategy. Rituximab is a human CD20-specific chimeric antibody extensively used in B-NHL therapy. We investigated whether conjugation to calicheamicin can improve the anti-tumor activity of rituximab against human B-cell lymphoma (BCL) xenografts in preclinical models. BCL cells were cultured with rituximab or its calicheamicin conjugates and their in vitro growth was monitored. BCL cells were injected s.c. to establish localized xenografts in nude mice or i.v. to establish disseminated BCL in severe combined immunodeficient (scid) mice. I.p. treatment with rituximab or its calicheamicin conjugates was initiated and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored. Conjugation of calicheamicin to rituximab vastly enhanced its growth inhibitory activity against BCL in vitro. Conjugation to calicheamicin had no deleterious effect on the effector functional activity of rituximab. Calicheamicin conjugated to rituximab with an acid-labile linker exhibited greater anti-tumor activity against s.c. BCL xenografts and improved survival of mice with disseminated BCL over that of unconjugated rituximab. Anti-tumor activities of rituximab conjugated to calicheamicin via an acid-stable linker were similar to that of unconjugated rituximab. Superior anti-tumor efficacy exhibited by a calicheamicin immunoconjugate of rituximab with an acid-labile linker over that of rituximab demonstrates the therapeutic potential of CD20-specific antibody-targeted chemotherapy strategy in the treatment of B-NHL.

Topics: Aminoglycosides; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody Specificity; Antigens, CD20; Cell Proliferation; Cytotoxicity, Immunologic; Drug Delivery Systems; Enediynes; Flow Cytometry; Humans; Immunoconjugates; Lymphoma, B-Cell; Mice; Mice, Nude; Mice, SCID; Rituximab