A HUMANIZED ANTITUMOR NECROSIS FACTOR-ALPHA MONOCLONAL-ANTIBODY THAT ACTS AS A PARTIAL, COMPETITIVE ANTAGONIST OF THE TEMPLATE ANTIBODY

We have constructed several humanized versions of a monoclonal antibod y (MAb78) against human tumor necrosis factor-alpha (huTNF-alpha) reta ining the complementarity-determining regions (CDR) of the original mo use MAb with or without a variable number of original framework region (FR) residues. All versions, except one, showed a loss of binding aff inity and neutralizing potency of at least 10-fold compared to the ori ginal mouse MAb or its chimeric equivalent. In some cases, however, th e decrease in neutralizing potency was significantly greater than the decrease in binding affinity. Two humanized versions showing the great est dissociation between these two parameters were studied for their c apacity to inhibit the neutralizing activity of chimeric or murine MAb 78 when used at concentrations that bound but only partially neutraliz ed huTNF-alpha. One humanized version (MAb78D) was indeed able to do s o, whereas the other (MAb78C) was not found to exert any inhibitory ac tivity at all concentrations tested. The antagonistic effect of MAb78D was concentration dependent and could be overcome by increasing the c oncentrations of chimeric or murine MAb78. Two different models of MAb 78-huTNF-alpha interaction that may help explain the antagonistic acti vity of humanized MAb78D are discussed.