As the founder, president and CEO of Advanced Proteome Therapeutics (TSX-V:APC; Frankfurt:OE8), Dr. Allen Krantz has successfully transitioned a career in academia to the biotech sector. From 1968 to 1974, he was a member of the Faculty of Chemistry at the State University of New York at Stony Brook and from 1974 to 1981 he held appointments in both the Department of Chemistry and the Department of Pharmacological Sciences in the Medical School at the same institution. Then he began an extensive career in industry, with senior research postings at Syntex Research Canada and RedCell, the forerunner of ConjuChem, including a stint as the Directeur Scientifique of the European office in France in the 1990s. Dr. Krantz was responsible for transforming the company’s program to a practical focal point on human serum albumin as a carrier of drugs. In 2007, Advanced Proteome was created through a reverse takeover. In this interview with BioTuesdays.com, Dr. Krantz discusses the company’s unique approach to developing a potential anti-cancer therapeutic.
Can you provide a brief overview of your technology?
Our technology combines multiple anti-cancer therapies, including immunotherapy, in a single agent to directly target cancer tumors. This type of agent is capable of greater potency, higher specificity, and less toxicity than the many therapies that can also attack healthy cells. The thrust of our current efforts is to combine our agents with other immunotherapeutics, such as checkpoint inhibitors, to achieve greater overall response rates and durable responses in patients than are currently observed in the clinic.
Can you elaborate on your delivery system?
We utilize a human protein as a delivery system, which may be thought of as having a homing instinct for a distinctive feature on the surface of cancer cells. This feature is not present on the surface of normal, healthy cells. Our proprietary technologies enable the site-specific attachment of various entities that endow the immunotherapeutic with additional functions to combat cancers. These protein modification technologies produce protein conjugates that consist of at least two entities linked together and meet the challenges of product homogeneity, the gold standard of manufacturing and drug development.
What are checkpoint inhibitors?
In humans, the immune system has evolved to determine which cells are friendly, and which cells should be destroyed. Checkpoint proteins provide “immunological brakes” to prevent the immune system from overreacting and causing injury to healthy cells and tissues. Normally, cells that are potentially cancerous are destroyed by the immune system, but if checkpoint inhibitors are displayed in certain ways and quantities on cell surfaces, the immune system may overlook key signals and allow cancer cells to proliferate. Checkpoint inhibitors are designed to lessen the effectiveness of checkpoint proteins, so that the cancer cells cannot evade destruction by the immune system. It makes much more sense therapeutically, to mobilize the immune system to clear cancer cells and instill memory for drug-free durable responses, than to directly attack cancer cells with chemotherapy which may likely develop drug resistance.
Checkpoint molecules put the brake on immune cells and can be tricked by cancer cells to do so. Checkpoint inhibitors are designed to ”take the brake off” and thus activate the immune system.
What restrictions do you see using checkpoint inhibitors on a stand-alone basis?
Despite the attractiveness of mobilizing the immune system by “removing one’s foot from the checkpoint brake” and allowing the immune system to more aggressively pursue cancer cells, such a strategy also has the potential for attacking healthy cells and causing severe immune-related adverse events. It is now established that most immunotherapies offer more benefit to the patient by being administered in combination with other forms of cancer management to prevent injury by an over-activated immune system.
What makes your approach so unique?
Advanced Proteome’s approach is unique in many respects.
First, we employ a human protein that has proven to enhance T cell mediated tumor immunity, and inhibit tumor growth in animals, an opportunity that others have neglected, which we have seized upon.
Secondly, clinical development of this protein as an anticancer agent depends critically on optimizing its properties. We have developed powerful proprietary technologies that are among the best in the field for modification of this protein, which are key to improving its anticancer activity, and are patent-protected.
Thirdly, we have demonstrated that our proprietary modifications, not only possess anticancer activity, but also exhibit synergies with checkpoint inhibitors in animal studies. Although other companies are pursuing combination therapies, it is most often the case that known off-patent molecules are being combined with checkpoint inhibitors. By contrast, not only are the company’s combination therapies unique, but also a major driver and value-added component of the combination are its proprietary protein modifications.
What are the big advantages of a combination therapy with checkpoint inhibitors?
The current excitement surrounding cancer immunotherapy stems from clinical data involving agents mediating immune checkpoint receptor blockade. These immunomodulators have displayed unprecedented efficacy (tantamount to cures in numerous patients) and durable responses against a range of tumors, compared with previous immunotherapeutic approaches. However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events. In light of the often spectacular clinical benefits observed after blockade of checkpoint receptors and data from preclinical mouse models, there is now a strong rationale to combine checkpoint inhibitors with other therapies to assess if clinical benefits to cancer patients can be further improved.
In short, the big advantages of using combination “cocktail” therapy with checkpoint inhibitors are the possibilities, with other efficacious molecules, of improving upon the often spectacular, but inconsistent efficacy of checkpoint inhibitors alone, that may also permit lower doses of individual components of the cocktail, thereby reducing adverse events observed with other therapeutic regimens.
Which checkpoint inhibitors you are using for your tests?
In addition to co-stimulatory molecules, we are using the full panoply of checkpoint inhibitors including anti-PD-1, anti-CTLA-4 and anti-PD-L-1 antibodies.
Tell us about the data you released in September?
Over the past year, we have demonstrated that our technology has the ability to overcome immune tolerance of certain tumors that have evolved mechanisms to evade attack by the body’s immune system. We have been able to enhance the affinity for target cancer cells of a natural human protein that possesses demonstrable anticancer activity, by modifying the protein chemically in a variety of ways. Indeed, various modifications of the protein, have translated into greater antitumor potency in animal models.
Now, results from combination therapy with checkpoint inhibitors have demonstrated very promising results with the first molecule tested from our inventory of modified proteins. In experiments with animal models with tumor implants carried out with our academic collaborators, checkpoint inhibitors by themselves only slowed tumor growth, but did not cause tumor regression. By marked contrast, in parallel experiments using a combination of a checkpoint inhibitor with our APC 101 protein modification, the tumors were eradicated. As well, subsequent experiments showed that the animals were immune to rechallenge by the same tumor.
What are your next important milestones?
Our principal focus at the moment is in demonstrating the breadth of anticancer activity of our protein modifications in diverse animal models. You only need to positively impact one major cancer, for example, lung cancer, to have a commercially successful company. However, the more animal models you can effectively treat, the more valuable the technology and the more effective your negotiating position is in prospective deals. Our company is moving with all deliberate speed by engaging contract organizations to complete a number of studies over the next several months.
