Compact disc20 is an important target for the treatment of B-cell

Compact disc20 is an important target for the treatment of B-cell malignancies including non-Hodgkin lymphoma MK 3207 HCl as well as autoimmune disorders. for the development of GA101 as a promising new therapy for the treatment of B-cell disorders. Introduction Rituximab a type I chimeric IgG1 anti-CD20 antibody has revolutionized the management and treatment of B-cell malignancies increasing the median overall survival of patients with many of these diseases.1 In combination MK 3207 HCl with chemotherapy it has significantly improved response rates and progression-free and overall survival of patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma.1 2 Rituximab treatment has also benefited patients with other diseases amenable to B-cell depletion therapy including B-cell Rabbit Polyclonal to CBX6. chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis.2 3 Nevertheless relapse is a common occurrence for example in B-CLL and there remains a need for treatments that delay the onset of relapse without increasing toxicity.1 To this end various therapeutic approaches are being explored including new chemotherapies small molecules antibody-drug conjugates and the use of alternative B-cell targets. However in contrast to the situation with rituximab the clinical benefit of these therapies remains to be demonstrated. In addition many of these agents exhibit poor safety and tolerability profiles or necessitate the use of more complex treatment regimens. Thus far CD20 has been the most effective unconjugated antibody target for the treatment of B-cell malignancies. An alternative and complementary approach is to MK 3207 HCl generate new unconjugated CD20 antibodies with enhanced functional activities that may lead to superior efficacy. Three types of functional activities of anti-CD20 antibodies have been described: signaling in target cells on CD20 binding leading to growth inhibition and (nonclassic) apoptosis (referred to as “direct cell loss of life”) complement-dependent cytotoxicity (CDC) and antibody-dependent mobile cytotoxicity (ADCC) mediated by cells exhibiting Fcγ receptors (FcγRs) such as for example MK 3207 HCl FcγRIIIa-expressing NK cells and macrophages.4 5 Anti-CD20 antibodies with different functions could be generated either (1) by selecting antibodies that bind to a new CD20 epitope which bind within an alternative mode or with changed affinity leading to altered strength or kind of functional system; or (2) by anatomist the Fc area from the antibody to improve immune effector features. The epitope and/or binding setting have been proven MK 3207 HCl to dictate 2 main types of Compact disc20 antibody effector function information termed type I or type II.5-7 Although both types I and II antibodies bind bivalently to Compact disc20 they form specific complexes with Compact disc20 as inferred from the fact that this B-cell surface can accommodate approximately double the number of type I antibodies compared with type II. Type I antibodies stabilize CD20 on lipid rafts leading to stronger C1q binding and potent induction of CDC. However this binding mode triggers only low levels of direct cell death. In contrast type II antibodies do not stabilize CD20 in lipid rafts and thus exhibit reduced binding to C1q and lower levels of CDC but they potently induce direct cell death.5 The majority of CD20 antibodies including rituximab veltuzumab 8 ocrelizumab 9 and ofatumumab 10 are of type I whereas the prototype type II antibody is the murine antibody B1 (tositumomab).11 The Fc region of rituximab plays a critical role in triggering the cellular events that lead to B-cell elimination in vivo.7 12 13 This region of the molecule can interact with match protein C1q and FcγRs to trigger CDC and ADCC respectively. Direct cell death mediated by rituximab does not involve the Fc region directly but could potentially be enhanced by Fc-mediated crosslinking via the C1q complex and FcγRs.5 Alternative type I CD20 antibodies have been generated including ofatumumab 14 15 AME-133 16 and a hexavalent anti-CD20 antibody.17 However superior maximal efficacy over rituximab that is efficacy at the saturation point of the dose-response curve has not been shown for any of these antibodies and their clinical efficacy compared with rituximab remains to be demonstrated. Our aim was to engineer a novel unconjugated agent against CD20 that displayed.