Chimeric TNT-3/human beta-glucuronidase fusion proteins for antibody-directed enzyme prodrug therapy (ADEPT).

ADEPT (antibody-directed enzyme prodrug therapy) is a novel therapeutic approach that targets an enzyme into tumors to convert a relatively nontoxic prodrug into an active cytotoxic agent. This method has a number of advantages, including the reduction of systemic toxicity, but to date it has not realized its full potential. A critical component of ADEPT is the choice of the monoclonal antibody (MAb) to target the enzyme into the tumor mass.

Comparison of recombinant derivatives of chimeric TNT-3 antibody for the radioimaging of solid tumors.

Although intact monoclonal antibodies (MAbs) are well suited as therapeutic reagents, their relatively slow clearance rates render them less useful for imaging applications. Over the last several years, our laboratory has developed a unique targeting approach to solid tumors that utilizes MAbs directed against DNA and its components to bind to degenerating cells and necrotic regions of tumors in a specific manner. Because these MAbs have considerable potential for the early diagnosis of cancer and for the monitoring of cytoreductive therapies, the availability of an effective imaging agent is highly desirable.

Stable, genetically engineered F(ab')(2) fragments of chimeric TNT-3 expressed in mammalian cells.

F(ab')(2) fragments are desirable structural derivatives of monoclonal antibodies (MAbs) because of their pharmacokinetic properties and bivalent binding to antigen. Production of these fragments, however, has proven difficult because of the variable sensitivity of intact antibodies to proteolytic enzymes, which can result in very low yields and unstable product. To circumvent these problems, we attempted to apply genetic engineering methods to generate stable F(ab')(2) fragments in NSO murine myeloma cells using the glutamine synthase expression system.

A new chemically modified chimeric TNT-3 monoclonal antibody directed against DNA for the radioimmunotherapy of solid tumors.

In the last several years, our laboratory has developed a new approach to the radioimmunotherapy of solid tumors, designated Tumor Necrosis Treatment (TNT), that exploits the presence of degenerating and necrotic cells within tumors by utilizing MAbs directed against universal, intracellular antigens. The first TNT MAb developed by our laboratory, designated TNT-1, was directed against nucleosomal determinants consisting of histone H1 and DNA. Since absolute tumor accretion of MAb is a critical determinant of antitumor efficacy in radioimmunotherapy, we sought to identify new antinuclear antibodies that displayed high tumor localization properties.

Potential role of the inactivated X chromosome in ovarian epithelial tumor development.

Background: Ovarian epithelial tumors can be divided into subcategories often regarded as different stages of neoplastic transformation. Cystadenomas belong to the least aggressive subgroup and are noninvasive and nonmetastatic. Ovarian tumors of low malignant potential (LMP) are intermediate between cystadenomas and carcinomas and show markedly reduced invasive and metastatic abilities.