title: Exhaustion of cytotoxic effector systems may limit monoclonal antibody-based immunotherapy in cancer patients.
abstract: The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial of OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), OFA treatment promoted partial CLL B cell depletion that coincided with reduced complement titers. Remaining CLL B cells circulated with bound OFA and covalently bound complement breakdown product C3d, indicative of ongoing complement activation. Presumably, neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining B cells. Instead, almost all of the bound OFA and CD20 was removed from the cells, in accordance with previous clinical studies that demonstrated comparable loss of CD20 from B cells after treatment of CLL patients with rituximab. In vitro experiments with OFA and rituximab addressing these observations suggest that host effector mechanisms that support mAb-mediated lysis and tumor cell clearance are finite, and they can be saturated or exhausted at high B cell burdens, particularly at high mAb concentrations. Interestingly, only a fraction of available complement was required to kill cells with CD20 mAbs, and killing could be tuned by titrating the mAb concentration. Consequently, maximal B cell killing of an initial and secondary B cell challenge was achieved with intermediate mAb concentrations, whereas high concentrations promoted lower overall killing. Therefore, mAb therapies that rely substantially on effector mechanisms subject to exhaustion, including complement, may benefit from lower, more frequent dosing schemes optimized to sustain and maximize killing by cytotoxic immune effector systems.
authors.affiliation: Genmab, 3584 CM Utrecht, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Beurskens
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farooqui
authors.forename: Paul V
authors.initials: PV
authors.lastname: Beum
authors.forename: Patrick
authors.initials: P
authors.lastname: Engelberts
authors.forename: Wendy J M
authors.initials: WJ
authors.lastname: Mackus
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
mesh_terms: D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor / Q000187:drug effects; D003131:Combined Modality Therapy; D003167:Complement Activation; D003179:Complement C3b / Q000032:analysis; D015935:Complement C4b / Q000032:analysis; D003165:Complement System Proteins / Q000276:immunology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018655:Lymphocyte Count; D009895:Opsonin Proteins / Q000276:immunology; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D009895:Opsonin Proteins; D000074323:Alemtuzumab; D000069283:Rituximab; D003179:Complement C3b; D015935:Complement C4b; D003520:Cyclophosphamide; D003165:Complement System Proteins; D014740:Vidarabine; C527517:ofatumumab; C024352:fludarabine