The candidate's immediate goal is to acquire critical scientific and clinical training to enable him to pursue independent investigation with a long-term goal of developing innovative therapies for non-Hodgkin's lymphoma (NHL). Incidence of NHL is increasing and improvements in therapy are needed. Radiolabeled antibody therapy has proven effective in treating NHL, but is limited by delivery of radiation to normal tissues due to circulating non-tumor bound radiolabeled antibody. The proposed program will integrate two complimentary approaches 1. preclinical development of a novel radioimmunotherapeutic approach and 2. clinical evaluation of radiolabeled antibody therapy. In preclinical studies, we hypothesize that rapidly removing circulating non-tumor bound radioisotope will decrease radiation delivered to normal tissues and improve relative radiation delivery to tumor. Specifically, our strategy involves exogenous administration of an enzyme, beta-lactamase, in order to cleave a circulating cephalosporin-based radioimmunoconjugate (RIC), resulting in rapid cleavage and removal of radioisotope from the body by the kidney. We further hypothesize the effectiveness of this approach will depend on stable intracellular retention of radioisotope in tumor and on more rapid tumor targeting. Biodistribution studies in murine and nonhuman primate models will b e performed with cleavable RICs that are internalized and retained by the tumor cell to ascertain if our approach will result in improvement in the delivery of radiation to tumor compared to normal tissues. In clinical studies, the candidate will assess the risk of secondary malignancies associated with myeloablative Iodine-131 anti-CD20 antibody and autologous stem cell transplant in patients with lymphoma previously treated and in ongoing trials. Furthermore, a proposed dose escalation trial in later years of this grant is anticipated with the optimized cleavable RICs developed in the preclinical proposal. In addition to these preclinical and clinical investigations, a rigorous didactic and mentoring program in clinical trial design will provide the candidate the foundation to implement and supervise clinical trials of novel therapies for NHL.
| Beeson, Craig; Butrynski, James E; Hart, Michael J et al. (2003) Conditionally cleavable radioimmunoconjugates: a novel approach for the release of radioisotopes from radioimmunoconjugates. Bioconjug Chem 14:927-33 |
