Anti-CD22/CD20 Bispecific antibody with enhanced trogocytosis for treatment of Lupus.
The humanized anti-CD22 antibody, epratuzumab, has demonstrated therapeutic activity in clinical trials of lymphoma, leukemia and autoimmune diseases, treating currently over 1500 cases of non-Hodgkin lymphoma, acute lymphoblastic leukemias, Waldenström's macroglobulinemia, Sjögren's syndrome, and systemic lupus erythematosus. Because epratuzumab reduces on average only 35% of circulating B cells in patients, and has minimal antibody-dependent cellular cytotoxicity and negligible complement-dependent cytotoxicity when evaluated in vitro, its therapeutic activity may not result completely from B-cell depletion. We reported recently that epratuzumab mediates Fc/FcR-dependent membrane transfer from B cells to effector cells via trogocytosis, resulting in a substantial reduction of multiple BCR modulators, including CD22, CD19, CD21, and CD79b, as well as key cell adhesion molecules, including CD44, CD62L, and β7 integrin, on the surface of B cells in peripheral blood mononuclear cells obtained from normal donors or SLE patients. Rituximab has clinical activity in lupus, but failed to achieve primary endpoints in a Phase III trial. This is the first study of trogocytosis mediated by bispecific antibodies targeting neighboring cell-surface proteins, CD22, CD20, and CD19, as demonstrated by flow cytometry and immunofluorescence microscopy. We show that, compared to epratuzumab, a bispecific hexavalent antibody comprising epratuzumab and veltuzumab (humanized anti-CD20 mAb) exhibits enhanced trogocytosis resulting in major reductions in B-cell surface levels of CD19, CD20, CD21, CD22, CD79b, CD44, CD62L and β7-integrin, and with considerably less immunocompromising B-cell depletion that would result with anti-CD20 mAbs such as veltuzumab or rituximab, given either alone or in combination with epratuzumab. A CD22/CD19 bispecific hexavalent antibody, which exhibited enhanced trogocytosis of some antigens and minimal B-cell depletion, may also be therapeutically useful. The bispecific antibody is a candidate for improved treatment of lupus and other autoimmune diseases, offering advantages over administration of the two parental antibodies in combination.
Immunomedics, Inc., Morris Plains, New Jersey, United States of America; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey, United States of America.
Edmund A
EA
Rossi
Immunomedics, Inc., Morris Plains, New Jersey, United States of America; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey, United States of America.
Chien-Hsing
CH
Chang
Immunomedics, Inc., Morris Plains, New Jersey, United States of America; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey, United States of America; Center for Molecular Medicine and Immunology, Morris Plains, New Jersey, United States of America.
David M
DM
Goldenberg
D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D008856:Microscopy, Fluorescence; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D000069283:Rituximab
D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D011947:Receptors, Antigen, B-Cell; C448700:epratuzumab; D000069283:Rituximab; C493846:veltuzumab