Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma

Abstract Obinutuzumab (GA101) is a novel glycoengineered type II CD20 antibody in development for non-Hodgkin lymphoma. We compared the anti-tumor activity of obinutuzumab and rituximab in preclinical studies using subcutaneous Z138 and WSU-DLCL2 xenograft mouse models. Obinutuzumab and rituximab were assessed alone and in combination with bendamustine, fludarabine, chlorambucil, doxorubicin and cyclophosphamide/vincristine. Owing to strong single-agent efficacy in these models, suboptimal doses of obinutuzumab were applied to demonstrate a combination effect. Obinutuzumab plus bendamustine achieved superior tumor growth inhibition versus rituximab plus bendamustine and showed a statistically significant effect versus the respective single treatments. Combinations of obinutuzumab with fludarabine, chlorambucil or cyclophosphamide/vincristine demonstrated significantly superior activity to rituximab-based treatment. Obinutuzumab monotherapy was at least as effective as rituximab plus chemotherapy in vivo, and obinutuzumab plus chemotherapy was superior to the respective monotherapies. These data support further clinical investigation of obinutuzumab plus chemotherapy.

[1]  D. Maloney.  Anti-CD20 antibody therapy for B-cell lymphomas. , 2012, The New England journal of medicine.

[2]  H. Pelicano,et al.  Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. , 2012, Blood.

[3]  D. Oscier,et al.  Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. , 2011, Blood.

[4]  C. Klein,et al.  Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. , 2011, Blood.

[5]  C. Klein,et al.  Comparison of the in vitro effects of the anti‐CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells , 2011, British journal of haematology.

[6]  C. Klein,et al.  Preclinical Studies on the Mechanism of Action and the Anti-Lymphoma Activity of the Novel Anti-CD20 Antibody GA101 , 2011, Molecular Cancer Therapeutics.

[7]  C. Klein,et al.  Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. , 2010, Blood.

[8]  F. Hagemeister.  Rituximab for the Treatment of Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukaemia , 2010, Drugs.

[9]  Yun Yen,et al.  NCCN clinical practice guidelines in oncology: hepatobiliary cancers. , 2009, Journal of the National Comprehensive Cancer Network : JNCCN.

[10]  C. Wittekind,et al.  Bendamustine - A New Approach to the Treatment of Advanced Hepatocellular Carcinoma? , 2008, Journal of chemotherapy.

[11]  A. Zelenetz,et al.  Treatment of follicular lymphoma: current status , 2008, Leukemia and Lymphoma.

[12]  W. Qian,et al.  Antitumor activity of fludarabine against human multiple myeloma in vitro and in vivo , 2007, European journal of haematology.

[13]  George Morstyn,et al.  Book Review: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval , 2004 .

[14]  C. Sautès-Fridman,et al.  FC GAMMA RECEPTOR , 2004 .

[15]  R. Mohammad,et al.  The addition of bryostatin 1 to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenograft model. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  C. Unger,et al.  Albumin Conjugates of the Anticancer Drug Chlorambucil: Synthesis, Characterization, and In Vitro Efficacy , 1998, Archiv der Pharmazie.

[17]  K. Tanikawa,et al.  Treatment of advanced hepatocellular carcinoma. , 1995, Internal medicine.

[18]  H. Otani,et al.  Effects of Chlorambucil on the Brain Development in Mice during Post‐neurulation Period , 1991 .

[19]  G. Pinkus,et al.  Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. , 1984, Blood.

[20]  E. C. Fieller.  SOME PROBLEMS IN INTERVAL ESTIMATION , 1954 .

[21]  W. N. Bailey.  An expression for , 1953 .

[22]  L. Tanoue,et al.  The National Comprehensive Cancer Network , 1998, Cancer.

[23]  D. Maloney.  Anti-CD 20 Antibody Therapy for B-Cell Lymphomas , 2012 .

[24]  R. Bharadwaj,et al.  Lymphoma and Chronic Lymphocytic Leukemias , 2010 .

[25]  B. Teicher,et al.  Anticancer Drug Development Guide , 1997, Cancer Drug Discovery and Development.

[26]  P. LoRusso,et al.  In Vivo Methods for Screening and Preclinical Testing , 1997 .

[27]  J. Ritz,et al.  A unique cell surface antigen identifying lymphoid malignancies of B cell origin. , 1981, The Journal of clinical investigation.