MONOCLONAL-ANTIBODY THERAPY OF B-CELL LYMPHOMA - SIGNALING ACTIVITY ON TUMOR-CELLS APPEARS MORE IMPORTANT THAN RECRUITMENT OF EFFECTORS

Despite the recent success of mAb in the treatment of certain malignan cies, there is still considerable uncertainty about the mechanism of a ction of anti-cancer Abs. Here, a panel of rat anti-mouse B cell mAb, including Ab directed at surface IgM Id, CD19, CD22, CD40, CD74, and M HC class II, has been investigated in the treatment of two syngeneic m ouse B cell lymphomas, BCL1 and A31. Only three mAb were therapeutical ly active in vivo, anti-Id, anti-CD19, and anti-CD40, mAb to the other Ags showed little or no therapeutic activity in either model despite giving good levels of surface binding and activity in ag-dependent cel lular cytotoxicity and complement assays, and in some cases inhibiting cell growth in vitro. We conclude that the activity of mAb in vitro d oes not predict therapeutic performance in vivo. Furthermore, in vivo tracking experiments using fluorescently tagged cells showed that anti -Id and anti-CD40 mAb probably operate via different mechanisms: the a nti-Id mAb cause growth arrest that is almost immediate and does not e liminate cells over a period of 5 or 6 days, and the anti-CD40 mAb hav e a delayed effect that allows tumor to grow normally for 3 days, but then abruptly eradicates lymphoma cells. This work supports the belief that mAb specificity is critical to therapeutic success in lymphoma a nd that, in addition to any effector-recruiting activity they may poss ess, in vivo mAb operate via mechanisms that involve cross-linking and signaling of key cellular receptors.