“Compelling Evidence for Re-design of Dosing Schedules in mAb-based Immunotherapy of Cancer: Lessons learned from CD20 mAbs”
Prof. Ronald Taylor University of Virginia, School of Medicine, Charlottesville, USA.
Time and location: March 14th at 13.30 MV Lecture Hall (Hörsalen), coffee and cake at 14.30
Prof. Ronald Taylor obtained his PhD from Princeton Uni. followed by postdoctoral education at Uni. of Minnesota after which he joined Uni. of Virginia where he became professor in 1983. For almost 30 years the Taylor laboratory has investigated monoclonal antibodies and their use in several different clinical applications with a particular emphasis on complement system. The laboratory first described the exhaustion of complement which follows high dose rituximab therapy in chronic lymphocytic leukemia (CLL) treatment. This work led to the discovery of the shaving/trogocytosis reaction: that is, the loss of CD20 that occurs when CLL patients are treated with the usual (high) doses of anti-CD20. More recently he described the complex series of events that occur when mAb-opsonized nucleated cells are killed by complement. These investigations, in collaboration with the biotech company Genmab, have revealed that it is the influx of calcium into the cells that is the most proximate mediator of complement-induced cell death.
Abstract: Rituximab and another CD20 mAb, ofatumumab, must use the body’s cellular and humoral immune effector functions to kill malignant cells. Although gram quantities of these mAbs can be administered to patients with chronic lymphocytic leukemia (CLL), our clinical and laboratory investigations reveal that effector mechanisms necessary for mAb activity are saturated/exhausted when tumor burdens are high. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted B cells by effector cells that express Fc receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. We propose that a low, frequent-dose strategy, based on administering 30–50 mg of CD20 mAb three times per week, should be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduces trogocytosis. This approach should have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and likely more efficacious for patients.
- CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering. Oostindie SC, van der Horst HJ, Lindorfer MA, Cook EM, Tupitza JC, Zent CS, Burack R, VanDerMeid KR, Strumane K, Chamuleau MED, Mutis T, de Jong RN, Schuurman J, Breij ECW, Beurskens FJ, Parren PWHI, Taylor RP. Haematologica. 2019 Feb 21. doi: 10.3324/haematol.2018.207266. [Epub ahead of print]
- Antibodies That Efficiently Form Hexamers upon Antigen Binding Can Induce Complement-Dependent Cytotoxicity under Complement-Limiting Conditions. Cook EM, Lindorfer MA, van der Horst H, Oostindie S, Beurskens FJ, Schuurman J, Zent CS, Burack R, Parren PW, Taylor RP. J Immunol. 2016 Sep 1;197(5):1762-75. doi: 10.4049/jimmunol.1600648. Epub 2016 Jul 29.
- Analyses of CD20 monoclonal antibody-mediated tumor cell killing mechanisms: rational design of dosing strategies. Taylor RP, Lindorfer MA. Mol Pharmacol. 2014 Nov;86(5):485-91. doi: 10.1124/mol.114.092684. Epub 2014 Jun 18. Review
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