Pfizer’s extensive and diverse portfolio of antibody-drug conjugates (ADCs) utilizes several conjugation chemistries and different linkers and payloads. Most conventional conjugation techniques used to produce antibody-drug conjugates (ADCs) result in a heterogeneous mixtures of ADC species with variable drug-to-antibody ratios (DAR) and loading distributions with potentially different pharmacokinetics, stability, and safety profiles. In an effort to overcome these challenges and produce homogeneous ADCs, an increasing number of site-specific conjugation technologies have been developed over the last decade.<br/>At Pfizer, Rinat developed an enzymatic process using bacterial transglutaminase (TG) to catalyze the reaction of glutamine residues in mAbs with amino groups of drug derivatives. Since endogenous glutamine residues (except C-terminal) are usually not recognized by the enzyme, the conjugation is specific to engineered glutamines or “glutamine tags” at designed sites in the mAb molecule.<br/>Presented will be case studies highlighting various aspects and challenges for the conjugation and purification process development of early phase clinical ADC candidates based on this enzymatic site-specific technology. Furthermore, considerations for the technology transfer spanning from research through development to clinical GMP manufacturing are addressed. This includes but is not limited to approaches to understand process parameters to control ADC key attributes, basic engineering principles and practices for the process scale up, and ensuring robustness across process scales.

Process development for the enzyme-mediated manufacture of site-specific ADCs for early clinical trials

253rd National Meeting (2017)

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