Biospecific Antibody Pretargeting for NHL

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Project 1 will evaluate pretargeting approaches based on bispecific antibodies (bsMAb) for the treatment of non- Hodgkin's lymphoma (NHL). The project will start with an evaluation of bispecific antibodies composed of a humanized anti-CD20 or an anti-CD22 that will be chemically coupled with a novel murine anti-histamine-succinylglycine (HSG) antibody. Working in collaboration with the Molecular Engineering and Antibody Production Core, recombinant anti-CD20 bsMAb will be prepared and subsequently tested. Recombinant bsMAb are expected to have more favorable pharmacokinetics yet equal binding properties as the chemically coupled bsMAb, making them more attractive agents for clinical use. The engineered bsMAbs will focus on the testing of a trivalent bsMAb that has divalent binding to the tumor target antigen with monovalent binding to HS.G. In vivo testing, biodistribution and therapy study designs, in SCID or nude mice bearing a human B-cell lymphoma xenograft will aid in determining specific parameters, such as bsMAb protein dose, interval spacing, and peptide dose that should be used to optimize this pretargeting procedure, and since a central hypothesis is that pretargeting will have advantages over a directly radiolabeled antibody, these comparisons will be made in collaboration with Project 2. A divalent HSG peptide will be used that has a single DOTA moiety forradiolabeling with 90Y, inln, and 177Lu. Tumor models mimicking micrometastatic disease and established disease will be examined to assess the optimal radionuclide for these conditions, as well as combination strategies with Auger-emitting^hLLl conjugates or with naked antibodies. This project will also examine a number of different strategies in vitro that might prove useful for encouraging the internalization of the pretargeted peptide or enhancing apoptosis, which may then be examined in vivo. Ultimately, Project 4 plans to initiate a clinical trial using this pretargeting approach with the recombinant bsMAb, and therefore this project will be instrumental in obtaining preclinical targeting and toxicity studies that will be used for the IND submission.