TOXINS TARGETED TO THE CELL MEMBRANE--DISRUPTION OF SIGNAL TRANSDUCTION

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This project seeks to develop agents which act by targeting a cell surface component of B-cell lymphomas which can negatively regulate cell growth by an effect on cellular signal transduction. These entities either as single agents or in combination with targeted deglycosylated ricin-A chain immunotoxins will be developed as novel therapeutic agents. The hypothesis to be explored is that the combined therapy with a targeted toxin and the negative growth regulatory molecule will lead to improved therapeutic index in comparison to that achieved by either agent alone. During the period of this report, this project has completed a Phase I clinical trial of IgG-HD37-SMPT-dgA, a toxin targeted at CD19. Of 10 patients treated, there were OcR, 1 PR, 2 MR, 2 SD, 4 PD, 1 NE, and a hitherto unreported toxicity, acral cyanosis, of IgG-HD37-SMPT-dgA was recognized. Interestingly, in correlative laboratory studies we observed that the antibody used to construct the toxin, HD37, was as active as the immunotoxin in decreasing cell proliferation in a CD 19-bearing lymphoma cell line. Studies with HD37 antibody reveal that within 12 hr of addition to exponentially growing cells, hypophosphorylation of pRb was observed, along with accumulation in G1. This result suggests the strategy of combining the antibody HD37 with IgG-RFB4-SMPT-dgA, a clinically active immunotoxin. A Phase I trial of the combination of IgG-RFB4-SMPT-dgA and IgG-HD37-SMPT-dgA is in progess and will provide the basis for comparing therapeutic index of the antibody plus immunotoxin combination.