Pretreatment with a monoclonal antibody/interleukin-2 fusion protein directed against DNA enhances the delivery of therapeutic molecules to solid tumors

The efficacy of molecular therapies for human malignancies is limited by in adequate accumulation within solid tumors. Our laboratory has developed a n ovel approach that uses monoclonal antibodies (MAbs) to direct vasoactive p roteins to tumor sites to increase local vascular permeability and, in turn , improve the delivery of therapeutic reagents. previously, we demonstrated that pretreatment with immunoconjugates containing interleukin-2 (IL-2) en hances specific tumor uptake of radiolabeled MAbs without affecting normal tissues. In the present study, we describe a fusion protein consisting of a chimeric antinuclear antibody and IL-2 (chTNT-3/IL-2) and illustrate its p otential for improving the delivery of both MAbs and drugs. The ability of pretreatment with chTNT-3/IL-2 to increase specific tumor uptake of the MAb B72.3 was demonstrated in LS174T colon tumor-bearing mice. Tumor accretion of B72.3 increased nearly 3-fold, with no changes in normal tissues. Abrog ation of this effect,vith N-G-methyl-l-arginine, a chemical inhibitor of ni tric oxide synthase, suggests that rapid generation of nitric oxide in the tumor is responsible for the enhanced uptake. To demonstrate that pretreatm ent with chTNT-3/IL-2 can improve the uptake of other clinically relevant M Abs in different tumor models, additional studies were performed in both lu ng and prostate xenograft models. Pretreatment with the fusion protein incr eased specific tumor uptake of the MAb NR-LU-10 in A427 lung tumor-bearing mice and enhanced tumor uptake of the MAb CYT-351 in LNCaP prostate tumor-b earing mice, 2.1-fold and 1.7-fold, respectively. Finally, tumor uptake of the radiolabeled thymidine analogue (125)IUdR also increased similar to 3-f old after pretreatment, indicating that this approach can be extended to sm all molecules such as chemotherapeutic drugs. Because TNT-3 recognizes a un iversal nuclear antigen accessible in degenerating and necrotic cells withi n all solid tumors, this strategy may be applicable to the majority of huma n cancers.