This month Regeneron Pharmaceuticals, a science-based biopharmaceutical company based in Tarrytown, New York and MedImmune, the global biologics research and development arm of AstraZeneca entered into a licensing agreement under which Regeneron will use MedImmune’s pyrrolobenzodiazepine (PBD)-based payload and linker technology to produce antibody-drug conjugates (ADCs) as potential, novel, cancer treatments.
ADCs are a promising area of cancer drug technology which may help enable the selective killing of cancer cells by combining a cytotoxic agent, sometimes referred to as a “warhead” or “payload,” with specific cancer-targeting monoclonal antibodies.
The pyrrolobenzodiazepine (PBDs) – used as “payload,” are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. They are significantly more potent than systemic chemotherapeutic drugs.
In vitro, pyrrolobenzodiazepines typically demonstrate IC50 values in the low to mid picomolar range in a variety of cell types, and unlike the anti-tubulin agents, they can induce cell death in both dividing and non-dividing cells. Fully synthetic PBD dimers are ideally suited for the role of payload in an antibody-drug conjugate because, unlike other cytotoxic payloads such as calicheamycin, they combine potency with a demonstrated therapeutic index, are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders such as maytansinoids and auristatins that currently dominate the antibody-drug conjugate arena.
The pyrrolobenzodiazepine (PBD) dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. Pyrrolobenzodiazepine dimers have been shown to have broad spectrum anti-tumour activity in vivo. These novel drugs exert their activity by binding in the minor groove of DNA and linking the two DNA strands together in a way that cells find difficult to recognise and repair.
The technology was originally invented and developed by Spirogen, a company acquired by MedImmune in 2013.
The two companies agreed that Regeneron will have exclusive rights to utilize MedImmune’s proprietary PBD technology to develop ADCs against a number of cancer targets, while MedImmune will have the option to develop and commercialize certain products created with this technology in territories outside of the United States.
“Developing next generation antibody-drug conjugates, including our proprietary PBD technology, is one of our key strategic platforms in advancing cancer therapies. Today’s collaboration represents our third partnership in this area, as we look to grow our ADC portfolio both internally and externally,” noted Ronald Herbst, Vice President, Oncology Research & Development, MedImmune. “We are pleased to be working with Regeneron, a company that is committed to advancing scientific innovation in cancer treatments. Regeneron’s research capabilities complements our commitment to discovering and developing the next generation of cancer therapies.”
Multiple innovative therapies and technologies
“We believe the most successful approaches to cancer R&D will combine multiple innovative therapies and technologies, and therefore we are pursuing a diverse array of strategies, pathways and modalities including ADCs, bispecific antibodies and monocolonal antibodies,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. “This new agreement will further bolster our efforts to advance new, effective treatment options for cancer patients in need.”
Regeneron’s clinical pipeline in oncology includes a PD-1 checkpoint inhibitor antibody, which is being developed in collaboration with Sanofi, and a CD20xCD3 bispecific. MedImmune is committed to advancing its pre-clinical and clinical stage ADC portfolio, in addition to its focus in immune-oncology, a strategy which rests upon the concept that the body’s own immune system can be unleashed or re-engaged to attack, eliminate or control cancer.
As part of the agreement, MedImmune will receive an upfront royalties on net sales of such products. Regeneron expects to advance multiple additional candidates into human clinical trials over the next 12 to 24 months.