title: Cytotoxic effects of the trifunctional bispecific antibody FBTA05 in ex-vivo cells of chronic lymphocytic leukaemia depend on immune-mediated mechanism.
abstract: Monoclonal antibodies such as rituximab and alemtuzumab show considerable therapeutic efficacy in chronic lymphocytic leukaemia (CLL). Aiming to further improve antineoplastic efficacy, the trifunctional bispecific antibody FBTA05 was developed. FBTA05 is thought to function by simultaneously binding B cells and T cells by its variable regions and by recruiting FcγR-positive accessory immune cells by its intact Fc region. As it was previously shown that this antibody shows considerable cytotoxicity towards a spectrum of B-cell lymphoma cell lines, we here tested its potential efficacy ex vivo against malignant B-CLL cells. Therefore, we assessed the capacity of increasing concentrations of FBTA05 to bind to neoplastic cells, to induce cytotoxicity (comparing it with rituximab and alemtuzumab) and cytokine release. We evaluated the results with respect to the extent of CD20 expression, the effector:target cell ratio as well as with the patients' overall effector cell status. Thus, we show that, although FBTA05-elicited cytotoxicity was comparable with that induced by alemtuzumab, it considerably exceeded the antineoplastic effects of rituximab. Noteworthy, FBTA05 shows effective elimination of malignant B cells even if CD20 surface expression is low. Importantly, a high grade of cytotoxicity was associated with the induction of T-cell proliferation and the concomittant release of interferon-γ and interleukin-6, thus overcoming the detrimental effects of an unfavourable effector:target cell ratio. In conclusion, we here present novel evidence for the therapeutic efficacy of the trifunctional, bispecific antibody FBTA05 in CLL and provide evidence for the importance of immune-mediated mechanisms conveying the cytotoxic effects against malignant B lymphocytes.
authors.affiliation: Service d'Hématologie Clinique, Hôpital Avicenne, AP-HP/Université Paris XIII, Bobigny, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
authors.forename: Petra
authors.initials: P
authors.lastname: Schroeder
authors.forename: Tina
authors.initials: T
authors.lastname: Mueller
authors.forename: Judith
authors.initials: J
authors.lastname: Atz
authors.forename: Kai Uwe
authors.initials: KU
authors.lastname: Chow
mesh_terms: D000074323:Alemtuzumab; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D018951:Antigens, CD20 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D054353:Perforin / Q000378:metabolism; D010641:Phenotype; D000069283:Rituximab; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C530113:Bi20 antibody; D016207:Cytokines; D054353:Perforin; D000074323:Alemtuzumab; D000069283:Rituximab; D053804:Granzymes