CHEMISTRY

Immunomedics' chemistry group focuses on the identification and preclinical development of tumor-associated therapeutic and diagnostic targeting agents. These agents include tumor-associated monoclonal antibodies (MAbs), receptor-targeting peptides and, more recently, combined antibody and peptide pretargeting combinations.

An important project has been the development of improved agents for radioimmunotherapy (RAIT) by combining humanized MAbs with an optimal high-energy nuclide for RAIT application, yttrium-90. The group was responsible for the development of the Company's technology for the facile and quantitative yttrium-90 (Y-90) radiolabeling of the hMN-14 and hLL2 antibodies. The generally applicable method relies on the use of macrocyclic chelate (termed DOTA) conjugates of the antibodies, and results in extremely stable Y-90 radiolabeled antibodies that are resistant to dissociation (Bioconjugate Chemistry 9:773-782, 1998). The proprietary hMN-14 and hLL2 MAbs are currently in Phase I clinical trials for the treatment of CEA-expressing solid tumors and non-Hodgkin's lymphoma.

Continuing research on RAIT has also recently led to the extension of our facile MAb radiolabeling technology to the medium/low energy emitter, lutetium-177 (Lu-177). This enables the same MAb conjugates to be used with two different radionuclides with distinct decay properties, thereby making the MAbs useful in patients with either large tumor deposits and/or micrometastases. Finally, we have developed novel methods for the improved labeling of internalizing MAbs with radioiodine, potentially making this radionuclide a much more attractive and effective agent for RAIT.

PEPTIDES

Many of our core radiolabeling technologies evolved from our original work on MAbs to receptor-targeting peptides. In turn, some of the radiolabeling methods developed for the peptide applications, together with our extensive prior radiolabeling experience, has led to novel radioimmunotherapy (RAIT) agents for application within 'pretargeting' formats.

PRETARGETING

'Pretargeting', as currently being developed by Immunomedics and IBC Pharmaceuticals, LLC (a subsidiary of Immunomedics) scientists, may allow a new generation MAb-based diagnostic and therapeutic agents to be developed. This approach uses a 'two-step' protocol. A humanized bispecific antibody (bsAb), with at least one arm that recognizes a tumor-associated antigen and at least one other arm that recognizes an epitope on a diagnostic or therapy agent, is given as a first injection. When non-tumor-targeted bsAb has substantially cleared non-target tissues and has reached a maximum level in the tumor, the bsAb-recognizable diagnostic or therapy agent is given. The latter agents either target to the bsAb localized at the tumor, or they are rapidly cleared through urine via the kidneys. In preclinical animal work, to date, high tumor to normal tissue localization ratios have been seen (Cancer Research 59:4400-4405, 1999), indicating excellent contrast for diagnostic purposes, and substantially improved ratios for therapy applications.

Importantly, our pretargeting methodology relies on the second arm of the tumor-targeting bispecific binding to a molecule that can be attached to any diagnostic or therapeutic agent. Because of this, the technology potentially comprises a universally useful system, not requiring the generation of a new second antibody for each and every individual diagnostic or therapeutic agent. Currently in preclinical studies are applications directed toward improved diagnostic agents based on technetium-99m for SPECT, and for the very sensitive detection modality, positron emission tomography. On the therapy side, we have expanded the range of useful 'two-step' therapy agents from radionuclides to anti-cancer chemotherapy drugs, ribonucleases, and enzyme prodrug therapy (ADEPT). Each of these applications is being studied either in our laboratories or in the collaborating laboratories of leading research institutions.

MOLECULAR BIOLOGY

This group of scientists is primarily focused on engineering the antibodies against diverse markers of cancer and infectious disease. This engineering includes humanization of the antibodies by recombinant DNA methodology, and constructing different forms of immunoglobulins and fragments derived therefrom. The humanized antibodies of the Company's Epratuzumab and Labetuzumab products have been patented by this group's scientists, as have also other molecular entities, such as fusion proteins and bispecific antibodies.