In pre-clinical xenograft studies using patient-derived breast cancer and non-small-cell lung cancer material, Synthon Biopharmaceuticals, a subsidiary of specialty pharma company Synthon, has reported promising, complete tumor remission with its lead program of antibody-drug conjugates (ADCs). Toxicity experiments conducted to-date have revealed Best-in-Class potential with a greatly improved therapeutic index compared to other armed antibodies, due to an impressive safety profile. The company has also opened a state-of-the-art GMP facility in Nijmegen, The Netherlands, for the production of ADCs up to phase III clinical trials and early launches.
Antibody-drug Conjugates or ADCs are a new type of targeted therapy that combines a specific anti-cancer antibody or antibody fragment linked to a potent anti-cancer therapeutic. The aim for this class of therapy is to combine better tumor penetration and killing properties with lower side effects for cancer patients.
Toxicity studies have revealed that clinically effective doses are not likely to show serious side-effects since the so-called therapeutic index has been improved with at least one order of magnitude compared to competitor ADC technologies…
Marco Timmers, Ph.D, chief scientific officer at Synthon Biopharmaceuticals noted: “Our first ADC program incorporates the HER2-binding antibody trastuzumab. The primary objective is to develop a broad therapeutic spectrum by targeting tumors that over-express HER2, such as metastatic breast cancer and non-small-cell lung cancer. As a result of our unique linker-drug technology, this ADC program is delivering on its promise and giving us exciting preclinical results with the opportunity to become a Best-in-Class therapy.”
In several xenograft models, including primary human breast cancer and non-small-cell lung cancer xenografts, Synthon’s HER2-ADC dosed alone induced complete tumor remission. In contrast, with the antibody alone there was no effect. Toxicity studies conducted to-date have revealed that clinically effective doses are not likely to show serious side-effects since the difference between effective and toxic doses, the so-called therapeutic index, has been improved with at least one order of magnitude compared to competitor ADC technologies.
Duocarmycin analogs and linker stability
Synthon’s proprietary ADC linker-drug technology is based on duocarmycin analogs. The differentiating design of the linker connecting the antibody to the duocarmycin drug, leads to high stability in circulation and also induces efficient release of the cytotoxin in the tumor cell. A key feature of Synthon’s duocarmycin technology involves disruption of the DNA of (solid) tumor cells at any phase of the cellular cycle unlike many other ADCs which only attack tumor cells in a mitotic state. Another feature of duocarmycins is that these cytotoxins can also be effective against tumor cells that are multi-drug resistant.
Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to elimination of the tumor cells. While the cytotoxins used by leading biopharmaceutical companies in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology is based on duocarmycin analogs, which have a unique mechanism of action.
Irreversible alkylation of DNA
These natural products, first isolated from Streptomyces bacteria in 1988, bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death. Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic state. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in case of solid tumors.
Another important benefit is that, unlike other drug classes, duocarmycins can be effective against tumor cells that are multi-drug resistant. For example, potent cytotoxicity has been demonstrated in cells that express the P-glycoprotein (P-gp) efflux pump. Multi-drug resistance presents a significant problem in the clinical setting and agents that are less susceptible to these mechanisms can successfully be used in prolonged treatment protocols. Although based on natural products, Synthon’s proprietary ADC linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to the duocarmycin drug, leads to high stability in circulation but also induces efficient release of the cytotoxin in the tumor cell.
With the newly opened GMP facility available, the company will enter its drug candidate into clinical trials in 2014. Timmers added: “We strongly believe that advancing this second generation ADC technology will lead to a new class of effective, targeted medicines in oncology. Our GMP plant will also accelerate future patient access to oncology products based on this pioneering technology.”
In addition to its ADC directed against HER2, Synthon is currently developing two other ADC programs for multiple indications in oncology. Depending on the indication, projects will be progressed independently until registration or will be co-developed/licensed out at an appropriate (pre-)clinical stage. The company also offers its linker-drug technology and manufacturing capabilities to external partners for conjugation to their own proprietary monoclonal antibodies.