These proposed studies will test the safety, bioactivity, pharmacokinetics and potential anti-tumor efficacy of IgG anti-transferrin (Tf) receptor antibodies in therapy of cancer. A variety of evidence indicates that dividing tumor cells require a continuous supply of iron obtained through surface Tf receptors, and suggest that transformed cells are less efficient than their normal counterparts in extracting iron through Tf. Pre-clinical in vitro and experimental in vivo studies conducted within a National Cancer Drug Discovery Group indicated that anti-Tf receptor antibodies inhibit Fe uptake from Tf and malignant cell growth, and have potential anti-cancer activity. A prior Phase I trial of an IgA anti-Tf receptor antibody showed such agents can be administered safely and inhibit peripheral iron uptake into tissues. The present trials extend those studies to simultaneous administration of two, non-cross-blocking anti-Tf receptor antibodies with demonstrated in vitro and in vivo anti-tumor cell activity. The IND for the clinical grade material has been developed in collaboration with the Division of Cancer Treatment and Cancer Treatment Evaluation Program of the National Cancer Institute. An initial single dose Phase I trial of two anti-Tf receptor antibodies administered simultaneously will be conducted. Laboratory studies will monitor in vivo effects on serum Tf receptor, Tf, serum iron, pharmacokinetics and delivery of antibodies to bone marrow cells. In vitro and in vivo studies will assess antibody effects on cytokine elaboration by macrophages. The initial trial will be followed by a Phase I/II multiple dose trial to evaluate the efficacy of this approach. This trial tests novel antibodies with a unique mechanism of anti-tumor activity and represents the first simultaneous administration of two antibodies targeted at the same antigenic target.
