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

Clin Cancer Res. 2015 Oct 1;21(19):4391-7. doi: 10.1158/1078-0432.CCR-15-0056. Epub 2015 May 11.

Abstract

Purpose: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models.

Experimental design: MCL cells were labeled with (51)Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. (51)Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose).

Results: Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL.

Conclusions: Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antigens, CD20 / metabolism
  • Antineoplastic Agents / pharmacology*
  • CD55 Antigens / metabolism
  • CD59 Antigens / metabolism
  • Cell Line, Tumor
  • Complement Activation / drug effects
  • Complement Activation / immunology
  • Complement System Proteins / immunology
  • Cytotoxicity, Immunologic / drug effects
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Humans
  • Lymphoma, Mantle-Cell / drug therapy
  • Lymphoma, Mantle-Cell / immunology*
  • Lymphoma, Mantle-Cell / mortality
  • Mice
  • Mice, SCID
  • Rituximab / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD20
  • Antineoplastic Agents
  • CD55 Antigens
  • CD59 Antigens
  • Rituximab
  • Complement System Proteins
  • ofatumumab

Associated data

  • ClinicalTrials.gov/NCT01527149