Due to the high response rates in normally untreatable tumors, development of checkpoint inhibitor antibodies is now dominating cancer therapeutic antibody development. Such antibodies act by inhibiting the interaction of tumor and immune cells (T-cells) that leads to suppression of a patient’s immune response. The competitors are numerous and Big Pharma are the leaders in the field. For the first time in drug development, Pfizer initiated simultaneously 11 Phase III registration trials for multiple cancer indications and they and other Big Pharma are buying rights and Companies with huge investments; all in a race to dominate a future $62 billion market. Perhaps the most important target identified to date is the system of PD-1 (on T-cell)/PD-L1 (on tumor).
The most important limitation to therapy with these antibodies has recently been reported: antigenic heterogeneity, with patients with low antigen expression having much lower response rates. Our technology overcomes this limitation allowing for treatment of even low expressing cancers while creating a more potent antibody.
We have taken 2 approaches for obtaining parent antibodies (before creation of an HD form); the first is generation of new antibodies with our partner using camelid and human libraries and the second is in-licensing a previously patented mAb to PD-L1. Both approaches are currently in proof-of-principle research.
[Vascular Endothelial Growth Factor (V-egf)]
Therapy aimed at the developing vascular endothelium of tumors is a proven target with the licensed product, Avastin, dominating the marketplace. This antibody acts by simply binding to V-egf and inhibiting its binding to its receptor. The patent on Avastin is due to expire in three years. Though licensing trials have demonstrated statistically significant responses, the responses are typically not durable and there is little impact on survival.
There are multiple explanations for the low efficacy of this therapeutic approach but certainly one likely explanation is that current mAbs targeting V-egf are not scavengers of V-egf but only act by temporarily blocking receptor binding. Therefore, without high levels of circulating antibody, newly synthesized or existing V-egf can act to promote blood vessel growth.
An HD- version of Avastin would have the advantage of longer occupancy of binding sites on V-egf due to its increased antibody binding and slower off-rate but could also act as a scavenger to remove V-egf from the body. This latter property is due to the HD version’s ability to create a lattice on the target which is then a trigger for opsonization and phagocytosis. We expect that an HD version of Avastin would be at least an order of magnitude better in inhibiting V-egf function.This product is in Preclinical Development.
Intellectual Property protection on many current therapeutic monoclonal antibody products have already or nearing patent expiration. This as seen as an opportunity by many other companies to develop their own biosimilar antibody which would compete in the market against the original product.
We are developing more potent versions of these off-patent antibodies. The most advanced HD forms are of Herceptin and Rituxin. We have demonstrated with HD-Herceptin that the HD form is at least 30 fold more active in animal models, is far more active in inducing apoptosis and recognizes low to intermediate Her-2 expressing tumors, a market not currently served by Herceptin.
HD-Rituxin has been shown to more active in inducing apoptosis, complement-mediated killing, and antibody-dependent cellular cytotoxicity than the parental form. We expect the HD form to also be more active in B-cell depletion, the product’s mechanism of action in both oncology and non-oncology applications.
Both HD antibodies have completed formal preclinical evaluation and are being readied for Phase I/II clinical trials.