Characterisation of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin's lymphomas
Jessica L Teeling, Ruth R French, Mark S Cragg, Jeroen van den Brakel, Marielle Pluyter, Haichun Huang, Claude H Chan, Paul W Parren, C E Hack, Michael Dechant, Thomas Valerius, Jan G van de Winkel, and Martin J Glennie*
Genmab, Utrecht, The Netherlands
Tenovus Cancer Research Laboratory, University of Southampton, Southampton, Hampshire, United Kingdom
Medarex, Princeton, NJ, USA
Sanquin Research, CLB and VU University Medical Center, Amsterdam, The Netherlands
Medicine I, University Schleswig-Holstein, Kiel, Germany
Genmab, Utrecht, The Netherlands; Immunotherapy, University of Utrecht, Utrecht, The Netherlands
Tenovus Cancer Research Laboratory, University of Southampton, Southampton, Hampshire, United Kingdom; Genmab, Utrecht, The Netherlands
* Corresponding author; email: mjg@soton.ac.uk.
Despite the rapid and widespread integration of chimeric CD20 mAb, rituximab, into the management of non-Hodgkin's lymphoma, its efficacy remains variable and often modest when used as a single agent. To develop more potent reagents, human immunoglobulin-transgenic mice were used to generate a panel of IgG1 CD20 mAb. All reagents bound strongly to CD20+ cells and recruited mononuclear cells for the lysis of malignant B cells. However, two mAb, 2F2 and 7D8, were exceptionally active in complement-dependent cytotoxcity (CDC), being able to lyse a range of rituximab resistant targets, such as CD20-low CLL, in the presence of human plasma or un-fractionated blood. Further analysis showed that 2F2 and 7D8, like rituximab, redistributed CD20 into Triton X-100 insoluble regions of the plasma membrane, but that they had markedly slower slow off-rates. To determine whether off-rate influenced CDC, a non-complement activating F(ab')2 anti-human kappa reagent was used. This reagent markedly slowed the off-rate of rituximab and increased its CDC activity to that of 2F2 and 7D8. Thus, with increasing evidence that mAb therapeutic activity in vivo depends on complement activation, these new CD20 reagents with their slow off-rates and increased potency in CDC hold considerable promise for improved clinical activity.
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