Catalent Pharma Solutions, a leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products, and Sanofi-Aventis Recherche & Développement, a member of Sanofi, an integrated global healthcare leader involved in the discovery, development and distribution of therapeutic solutions, have agreed to collaborate  in the development of next generation Antibody-drug Conjugates (ADCs).

As part of the agreement, Sanofi will to implement Catalent’s proprietary SMARTag™ technology in the development of future – next-gen – Antibody-drug Conjugates. One problem with the available antibody-drug conjugate technology is that is remains difficulty to create conjugates with a uniform drug to antibody ratio (DAR) and consistent payload placement on the antibody.

In an article published in the July 2014 edition of Bioconjugate Chemistry, Drake et al explains that site-specific conjugation offers significant advantages over conventional conjugation chemistries used to make antibody-drug conjugates. Site-specific payload placement, for example, allows for control over both the drug-to-antibody ratio and the conjugation site, both of which play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of the ADC. Furthermore, in addition to the DAR and site of conjugation, linker composition also plays an important role in the properties of an ADC. [1]

To date, frequently used conjugation chemistry to attach cytotoxic payloads to antibodies for the generation of antibody-drug conjugates  rely either on a reaction with antibody cysteine or lysine residues.

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Because antibodies contain many of both residues and conjugation using either chemistry does not occur reproducibly at every site, mixtures of ADCs will show a range of variable drugs per antibody as well as placement at different locations. As a result of the uncontrolled payload and position, manufacturing ADCs reproducibly can be a significant challenge.  Furthermore, the variations in loading each distinct conjugate results in a different efficacy, toxicity and pharmacokinetic profile.

Photo: Barry Littlejohns, President Catalent Advanced Delivery Technologies. Photo Courtesy: Catalent

SMARTag, a proprietary site-specific protein modification and cytotoxin-linker technologies developed by Redwood Bioscience Inc., which was acquired by Catalent Pharma Solutions in late 2014, offers an alternative process of generating ADCs to produce uniform conjugates. Then technology ables the generation of homogenous bioconjugates engineered to enhance potency, safety and stability.[2]

SMARTag technology uses natural post translational modifications found in human cells to create one or more aldehyde tags at designated sites on protein molecules. These chemical handles are then stably conjugated to cytotoxic payloads to prevent their systemic release. Using precision chemistry, 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.[2]

Enhancing pharmacokinetics, efficacy and safety
As part of their collaboration, the companies agreed that Catalent will develop site-specifically modified antibody conjugates using Sanofi’s proprietary antibodies. The precision protein-chemical engineering approach developped by Catalent enables Sanofi to evaluate site selective payload conjugation in order to enhance ADC pharmacokinetics, efficacy and safety.

The collaborative work will involve teams at Sanofi, and Catalent’s facility, in Emeryville, CA, which was formerly headquarters to Redwood Bioscience Inc. Catalent announced in October 2014 that it had purchased the remaining stake in Redwood, following the successful achievement of in vivo and in vitro proof of concept milestones, recent compelling in vivo toxicology data, and strong customer interest in the SMARTag technology.

“We [..will..] jointly work toward the goal of creating better drugs to meet patient needs,” commented Barry Littlejohns, Catalent’s President of Advanced Delivery Technologies. “Through in vivo toxicology studies, we have demonstrated that ADCs generated using Catalent’s SMARTag platform have a better toxicity profile than a conventional ADC, while efficacy studies also point to an improved therapeutic index.”

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