The goal of this program is to develop a therapeutic approach for metastatic breast cancer using biologically active humanized radioimmunoconjugates combined with other biologic response modifiers (BRM's). In this proposal we plan to combine a select set of BRM's for therapy of advanced breast cancer in a programmed manner calculated to achieve clinical responses while evaluating possible mechanisms to achieve synergistic tumor cytotoxicity. The molecular immunology group in this program will seek to humanize selected MoAbs which they have previously developed to defined molecular targets associated with breast cancer. MoAb BrE-3, has now been humanized (HuBrE-3) while retaining its high antigen binding affinity. Further attention will be placed on control of such biologic activities as demonstrated by ADCC and CDC. The specific MoAb's chosen for clinical study will be selected on the basis of their possible addition to the therapeutic potential...i.e. further enhancement of in vivo effector cell activation, complement mediated tumor cytolysis or effect on growth regulating molecules. Pharmacokinetics and radiation dosimetry derived from quantitative imaging will provide the method for judging the effect of these approaches on the therapeutic index and correlation will be made with therapeutic response. Strengths of this project include an investigative team that has a record of accomplishments with clinical radioimmunotherapy and BRM's, and who has directly attacked the problems that must be resolved to successfully use this therapy for solid tumors. The results from the studies described in this proposal utilizing humanized biologically active MoAbs, advanced radioconjugates, stem cell growth factors and other BRM's holds significant therapeutic potential. This investigation will provide information that is generally applicable to treatment with other radiolabeled bioengineered molecules in combined therapeutic endeavors and we believe this approach will result in significant therapeutic response at well tolerated dose levels.
