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Ofatumumab Exhibits Enhanced in Vitro and in Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma Matthew J

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Ofatumumab Exhibits Enhanced in Vitro and in Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma Matthew J Published OnlineFirst May 11, 2015; DOI: 10.1158/1078-0432.CCR-15-0056 Cancer Therapy: Preclinical Clinical Cancer Research Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma Matthew J. Barth1, Cory Mavis2,3, Myron S. Czuczman2,3,and Francisco J. Hernandez-Ilizaliturri2,3 Abstract Purpose: Mantle cell lymphoma (MCL) is a mature B-cell CD59 were measured by Imagestream analysis. SCID mice inoc- lymphoma considered to be incurable with current treatments, ulated subcutaneously with Z138 cells were assigned to control including first-line rituximab in combination with multiagent versus four doses of ofatumumab or rituximab (10 mg/kg/dose). chemotherapy and for those eligible, high-dose chemotherapy Results: Ofatumumab exhibited enhanced in vitro comple- and stem cell support or rituximab maintenance. On the other ment-dependent cytotoxicity activity compared with rituximab hand, achieving a complete remission by high-sensitive flow in MCL cell lines, despite a high degree of in vitro resistance to cytometry is associated with prolonged duration of remission, rituximab associated with low CD20 levels and/or high expres- stressing the need to develop and/or incorporate novel agents into sion of complement inhibitory proteins. Ofatumumab also the management of MCL. To this end, we examined the activity of delayed tumor progression and prolonged survival in a murine ofatumumab, an anti-CD20 monoclonal antibody with distinct model of MCL. binding and immunologic properties compared to rituximab, in Conclusions: Our results demonstrate that ofatumumab is MCL preclinical models. more effective than rituximab in MCL preclinical models, includ- Experimental Design: MCL cells were labeled with 51Cr before ing in the presence of rituximab resistance, and support the incubation with rituximab or ofatumumab (10 mg/mL) plus clinical investigation of ofatumumab in combination with stan- human serum or effector cells. 51Cr-release was measured and dard systemic chemotherapy in MCL (NCT01527149). Clin Cancer the percentage of lysis was calculated. Surface CD20, CD55, and Res; 1–7. Ó2015 AACR. Introduction The addition of the anti-CD20 mAb rituximab to chemother- apy regimens has improved overall survival (OS) in indolent and Mantle cell lymphoma (MCL) is a mature B-cell non-Hodg- aggressive B-NHL, though patients frequently relapse with disease kin lymphoma (B-NHL) characterized by overexpression of that demonstrates variable degrees of sensitivity to retreatment cyclin D1 resulting from the translocation t(11;14; ref. 1). MCL with rituximab containing regimens (3–6). The addition of ritux- represents about 2% to 10% of B-NHL. Frequently presenting imab to chemotherapy in treating MCL has also been shown to with advanced stage disease, MCL is generally considered to be improve clinical outcomes, including OS (7). Despite the survival incurable with current treatment regimens that incorporate benefit with the addition of rituximab, nearly all MCL patients high-dose cytarabine, rituximab, anthracycline-based multia- eventually relapse and novel treatment approaches are needed to gent chemotherapy regimens (i.e., CHOP) and, for those eli- further improve outcomes. gible patients, high-dose chemotherapy with autologous stem In order to improve on the advances achieved in the era of cell support (HDC-ASCS). Despite a high response rate rituximab in treating B-NHL, it is important to gain an under- observed to upfront therapy and significant prolongation in standing of factors that contribute to the antitumor activity of or to survival with modern treatment regimens, the disease is still the development of resistance to rituximab. Potential factors that characterized by continuous relapses and acquirement of resis- affect rituximab activity include genetic polymorphisms in the Fc tance to subsequent treatments resulting in a median survival receptor, decreased CD20 expression, and increased complement of only 3 to 5 years postdiagnosis (2). inhibitory protein (CIP) expression (8–11). Multiple next-gener- ation anti-CD20 mAbs with variable mechanisms of activity have been developed and are currently under evaluation in the treat- 1Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New ment of B-NHL. York. 2Department of Immunology, Roswell Park Cancer Institute, Ofatumumab is a humanized anti-CD20 mAb that is currently Buffalo, New York. 3Department of Medicine, Roswell Park Cancer Federal Drug Administration (FDA) approved for the treatment of Institute, Buffalo, New York. refractory chronic lymphocytic leukemia (CLL; ref. 12). Ofatu- Corresponding Author: Matthew J. Barth, State University of New York at mumab binds to a unique, more membrane-proximal epitope on Buffalo, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-2333; Fax: the CD20 antigen (13). In preclinical models, ofatumumab has 716-845-8003; E-mail: [email protected] demonstrated similar antibody-dependent cellular cytotoxicity doi: 10.1158/1078-0432.CCR-15-0056 (ADCC) activity with enhanced complement-dependent cytotox- Ó2015 American Association for Cancer Research. icity (CDC) activity compared with rituximab and more efficiently www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst May 11, 2015; DOI: 10.1158/1078-0432.CCR-15-0056 Barth et al. Translational Relevance patients with B-cell NHL treated at Roswell Park Cancer Institute (RPCI, Buffalo, NY) procured under Institutional Review Board Mantle cell lymphoma (MCL) is generally considered incur- (IRB) RPCI protocols I42804 and I42904. Tissue specimens able with modern treatment regimens that incorporate ritux- were placed in PBS-containing collagenase type IV (1 mg/mL; imab with combination chemotherapy regimens. In preclin- Sigma-Aldrich) and incubated for 15 minutes at 37C, including ical testing, novel anti-CD20 monoclonal antibodies have manual agitation for five minutes. Next, samples were diluted demonstrated variable degrees of increased activity, when with RPMI-1640–containing 10% FBS and the cell suspension compared with rituximab, against a variety of CD20-expres- filtered through a 100-mm cell strainer to remove large clumps. sing malignancies. In this study, we found that the anti-CD20 Subsequently, lymphocytes were enriched by histopaque den- monoclonal antibody ofatumumab exhibits more potent sity centrifugation. B cells were then isolated from enriched activity compared with rituximab against MCL cells in vitro lymphocytes by MACS separation using a human B-cell Isola- and in vivo, including in cell lines with significant in vitro tion Kit II (Miltenyi Biotec). Cells were incubated with ofatu- resistance to rituximab associated with high levels of expres- mumab, rituximab, isotype, or media with 25% human serum. sion of the complement inhibitory proteins CD55 and CD59, After 48 hours, cell viability was determined by Cell-Titer Glo which have previously been correlated with decreased ritux- assay (Promega). imab-associated cytotoxicity. Our work supports the further development of ofatumumab in the treatment of MCL. Functional cytotoxicity assays of ofatumumab and rituximab- induced ADCC and CDC Standard 51Cr release assays were performed to assess anti- CD20 mAb-mediated CDC and ADCC. For CDC and ADCC assays, 5 Â 106 MCL cells were labeled for 2 hours at 37C with in vivo – induces B-cell depletion (14 16). Ofatumumab is currently 3.7MBq of 51Cr (100 mCi). Subsequently, 1 Â 105 cells/well or 1 Â € under investigation in clinical trials in both treatment na ve and 104 cells/well were placed in 96-well plates for CDC or ADCC relapsed/refractory indolent and aggressive B-NHL, including assays, respectively. MCL cells were then exposed to RPMI-1640, MCL. ofatumumab, rituximab, or isotype control at a final concentra- in vitro in vivo We have previously reported on the enhanced and tion of 10 mg/mL in combination with human serum (dilution fi ef cacy of ofatumumab against Burkitt's lymphoma (BL) and 1:4, CDC assays) or peripheral blood mononuclear cells (PBMC) diffuse large B-cell lymphoma (DLBCL) preclinical models, at an effector:target ration of 40:1 (ADCC assays). Pooled human including in the setting of acquired rituximab resistance (17). To serum and PBMCs were collected from healthy donors under further characterize the activity of ofatumumab against MCL cells, RPCI IRB-approved protocol CIC 01-16. PBMCs were obtained by we performed preclinical testing in cytarabine-sensitive and -resis- Ficoll-Histopaque centrifugation of whole blood as previously in tant MCL cell lines, primary patient-derived MCL cells and in described (20). Cells were incubated at 37C, 5% CO for 6 hours. vivo 2 SCID mouse xenograft models of human MCL. A set of 51Cr-labeled NHL cells was incubated in RPMI-1640 and then treated with 50 mL of a 5% Triton solution to determine Materials and Methods maximum cell lysis. Finally, the 96-well plates were centrifuged at MCL cell lines and cytarabine-resistant MCL cell lines 2,000 rpm for 5 minutes and the supernatant of each well was Experiments were conducted in several cytarabine-sensitive and collected; gamma emission was measured by the Packard Auto- cytarabine-resistant MCL cell lines. The sensitive cell lines Granta, Gamma Cobra II series counting system (IBM Inc.). Percentage of HBL-2, Jeko-1, Mino, and Rec-1 were purchased from DSMZ and 51Cr release (lysis) was calculated using
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