ADC Surrogates for Process Development

The team will demonstrate the physicochemical similarity of candidate fluorhead-linker conjugates to two warhead-linker conjugates in current use in ADCs: an auristatin-based conjugate (MMAE-SMCC) and a pyrrolobenzodiazepine-based conjugate (PBD-SMCC).

Industry Need

Antibody-drug conjugates (ADCs) are high-potent active pharmaceutical ingredients that compromise chemotherapy agents coupled to tumor-target antibodies. However, ADCs are extremely toxic in concentrated forms present in manufacturing and analytical settings.

Approach

The team aims to make surrogate ADCs "sADCs", that will have similar chemical size and structure without the extreme toxicity.

Impacts

sADCs will facilitate exploratory process research and development for work ADCs by manufacturers and vendors.

For the analytical chemistry/process analytical technology discipline, sADCs can serve as a convienent analytical reference/calibration standard for critical quality attribute asessment and facilitate the development of new analytical technologies.

Value Statement/Outcomes

By implementing surrogate ADCs (sADCs) with novel fluorhead-linker compounds such as SMCC-AS20 and Mal-PEG12-PS19, organizations can reduce containment and occupational safety infrastructure costs while accelerating ADC process development through safe, scalable conjugation in standard suites. This approach enables robust analytical method development and calibration, ensuring consistent product quality and regulatory compliance without exposure risk.

Outputs/Deliverables

The project team have synthesized a novel linker-“fluorhead” fluorescent compound, “SMCC-AS20”, that is a close structural and hydrophobicity mimic for the auristatin-based linker-warhead compound SMCC-MMAE. Similarity was assessed via comparative structural analysis, computational analysis and RP-HPLC retention analysis; properties were found to be an excellent match. Subsequent preparative-scale synthesis yielded 0.3 grams of material. SMCC-AS-20 is ready for conjugation to target mAbs for the production and characterization of surrogate ADCs.

The project team have synthesized a novel linker-“fluorhead” fluorescent compound, “Mal-PEG12-PS19”, that is a close structural and hydrophobicity mimic for the pyrrolobenzodiazepine dimer-based linker-warhead compound tesirine. Similarity was assessed via comparative structural analysis, computational analysis and RP-HPLC retention analysis; properties were found to be a good match. Subsequent preparative-scale synthesis of Mal-PEG12-PS19 yielded 0.4 grams of material. Mal-PEG12-PS19 is ready for conjugation to target mAbs for the production and characterization of surrogate ADCs

Posters

Hasija, N., Armitage, B. A., Davis, J., McDermott, L., Ramsay, J., Pappas, D., Goundry, W., Schneider, J. W., & Przybycien, T. M, Fluorheads for Process Development of Antibody-Drug Conjugates, Gordon Research Conference on Biotherapeutics and Vaccines Development, Ventura, CA, March 27, 2022.

Przybycien, T., Presenter, PC2.2-109 Linker-“Fluorhead” Conjugates for the Production of Surrogate ADCs, NIIMBL National Meeting, Washington, D.C., July 27, 2022.