Results of an in vivo toxicology study, demonstrates that an Antibody Drug Conjugate or ADC generated using the proprietary SMARTag™ platform has a better toxicity profile than a conventional ADC. The study, conducted in a rat model by scientists at Redwood Bioscience, Inc.(Emeryville, CA), a company developing precision protein-chemical engineering technology to produce next-generation antibody-drug conjugates and other semi-synthetic biotherapeutics, compared the effects of a single dose of 6, 20 or 60 mg/kg of a SMARTag ADC conjugated to a cytotoxic payload using the proprietary HIPS chemistry, to an ADC generated with traditional conjugation methods.
The researchers found that the SMARTag ADC was well tolerated and provided statistically significant survival benefits versus the conventional ADC, particularly at high doses where the conventional ADC resulted in mortality. Elevations in liver enzymes and decreases in platelet counts and reticulocytes were also observed with the conventional ADC at 20 and 60mg/kg treatments, whereas these effects were only seen with the highest dose of the SMARTag ADC. In addition the toxicokinetic analysis showed that the SMARTag ADC had greater exposure and longer circulating half-life than the conventional ADC comparator.
Redwood’s proprietary SMARTag site-specific protein modification and cytotoxin-linker technologies enable the generation of homogenous bioconjugates engineered to enhance potency, safety and stability. The technology employs natural post translational modifications found in human cells to site specifically create one or more aldehyde tags on protein molecules. These chemical handles are then stably conjugated to cytotoxic payloads to prevent their systemic release. The SMARTag platform provides precise payload positioning and defined stoichiometry of payload–protein ratios. The control afforded by the technology enables identification of superior drugs from libraries of differentially designed conjugates.
This unique chemistry results in a stable C-C bond between the antibody and the cytotoxin payload. In comparisson to other linker chemistries, this creates a uniquely stable connection.
The site-specific payload placement – using SMARTag – allows for control over both the drug-to-antibody ratio or DAR and the site of conjugation. Both play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of an ADC. In addition, linker composition also plays an important role in the properties of an ADC.
David Rabuka, PhD, Founder and President and Chief Scientific Officer of Redwood Bioscience, noted: “In summary, the study showed that the SMARTag ADC was a less toxic treatment and, taken together with the efficacy studies, points to an improved therapeutic index for the SMARTag ADC compared to the conventionally conjugated ADC.”
“This data provides further evidence of the potential benefits the SMARTag technology offers our customers developing next-generation ADC therapies, and their patients,” added Barry Littlejohns, President, Advanced Delivery Technologies, Catalent Pharma Solutions (Somerset, NJ).