Our research is focused upon exploiting engineered antibody fragments to both detect and treat solid tumors. To accomplish this, we are using phage display and hybridoma technology to develop new antibodies specific for novel tumor antigens. Antibodies that successfully target tumors in vivo are employed either in an unconjugated form to directly inhibit tumor growth or used as vehicles for the delivery of cytotoxic agents that can kill the tumor cells or poistron-emitting radioisotopes to facilitate ImmunoPET tumor detection. We are also examining the impact of antibody affinity on tumor targeting and penetration and the use of heterodimeric constructs to enhance targeting specificity.
Antibodies that exhibit tumor specificity but do not directly inhibit tumor growth can be employed to deliver cytotoxic drugs, catalytic toxins or radioisotopes to tumor sites. We have employed dimeric single-chain Fv fragments, known as diabodies, to deliver alpha-emitting radioisotopes (e.g., Bi-213, At-211) and intermediate-lived beta emitting isotopes (e.g., Y-90 and I-131). In preclinical models, we have observed that an anti-HER2 diabody labeled with these radioisotopes can mediate significant delays in tumor growth. We are also examining the efficacy therapywith catalytic toxins, such as saporin, conjugated to antibodies that are specifically internalized into tumor cells.
The EGFR family of transmembrane proteins, composed of HER2 (HER2/neu or c-erbB-2), HER3 (c-erbB-3), HER4 (c-erbB-4) and EGFR has been identified as having an important role in many types of cancer. The members of this growth factor receptor family are overexpressed in a large variety of carcinomas. Antigen bridging is involved in most antibody-triggered signal transduction. However, naturally occurring antibodies can only bind to two identical epitopes, thus leading to the bridging of two identical molecules (e.g., two HER2). Since a major pathway in the signal transduction by elements of the EGFR family involves the heterodimerization of HER2 with HER3 or HER4, it follows that antibodies designed to stimulate or perturb this process should also be heterodimeric in nature. Accordingly, we have created and are evaluating scFv molecule heterodimers that target pairs of the members of the EGFR family.
While PET imaging with 18FDG is rapidly becoming commonplace in the diagnosis of patients with cancer, many types of tumors (e.g., Prostate cancer) are not FDG-avid. Recent efforts to develop antibody-based targeting strategies for PET isotopes have been limited due to the short physical half-life of the commonly available PET isotopes (e.g., F-18) and unacceptable retention of the radioisotopes (e.g., Cu-64 and I-124) in the kidneys and liver. To address this, we are employing engineered antibody fragments to deliver PET radioisotopes to tumors.
The Müllerian Inhibiting Substance Type II Receptor (MISIIR) plays a critical role in the regression of the female reproductive tract in males during fetal development. MISIIR is expressed on the surface of human ovarian cancer cells and these cells apoptose in response to treatment with the Müllerian inhibiting substance (MIS). We have produced recombinant MISIIR and have used it to isolate antibodies that specifically target this receptor. We are currently evaluating these antibodies for direct therapeutic potential and for their ability to selectively target cytotoxic agents to ovarian tumors.