Antibody-Drug Conjugate Therapeutic Window Enhancement

In this webinar, antibody-drug conjugate (ADC) experts Zhala Tawfiq, from Aji Bio-Pharma Services, and Yutaka Matsuda, from Ajinomoto Inc., discuss advantages of next generation ADC technologies, specifically, Ajinomoto’s proprietary site-specific conjugation technology called “AJICAP.”

ADCs are potent, anti-tumor targeting molecules that combine monoclonal antibodies with highly potent cytotoxic compounds, via a chemical linker, and have recently become a major class of cancer biopharmaceuticals. Traditional ADCs are synthesized by lysine or cysteine chemistries, and this results in a stochastic distribution of cytotoxic drugs on different sites of the antibody. The heterogeneous nature of these stochastic ADCs can cause diminished efficacy and increased toxicity, thus limiting the corresponding therapeutic index.

To improve on traditional ADC technology, we developed and report here a novel chemical conjugation platform termed “AJICAP” for the site-specific modification of native antibodies through the use of a class of IgG Fc-affinity reagents¹. Site-specific installation of thiol functional groups to well-defined lysine residues in IgGs, followed by cytotoxic payload conjugation to these newly installed thiols, was efficiently conducted to generate AJICAP-ADCs. Conjugation site location was confirmed by peptide mapping, and Q-TOFMS analysis showed that the Drug Antibody ratio (DAR) was approximately 2².

The Aji Bio-Pharma team demonstrated that the technology could be scaled to produce gram-scale quantities of ADCs for pre-clinical testing. The process developed for the “Gram-Scale” AJICAP conjugation batch utilized scale-down manufacturing and purification procedures³. The minimum yield of each step was 91% and more than 1.4 g AJICAP™-ADC was synthesized to establish good manufacturing strategy⁴. Additionally, the stability assessment of the thiol-modified antibody synthesized by AJICAP technology indicated no appreciable increase in aggregation nor decomposition upon prolonged storage. This intermediate can be useful in payload and linker screening studies, as well as a potential hold-point in an ADC manufacturing process. Furthermore, payload conjugation with this stable thiol intermediate generated several AJICAP-ADCs which were biologically evaluated. The biological studies demonstrated an expansion of the AJICAP-ADC therapeutic window, compared with stochastic conjugation technology.

To further our development in novel, next generation ADC technologies, we are also developing and introducing a novel cleavable linker to increase ADC stability in vivo, demonstrating that this novel cleavable linker is responsive to enzymatic drug release but undergoes almost no premature cleavage. The combination of AJICAP technology and novel cleavable linkers exhibited greater stability and efficacy than traditional valine-citrulline linker-based ADCs.

Overall, our site-specific conjugation technology coupled with a novel cleavable linker, reduces heterogeneity, thus simplifying manufacturing and characterization of the ADCs, and enhances biological properties by increasing the therapeutic window. These proprietary ADC technologies bring significant advantages and are a powerful platform to enable next-generation ADCs.

1. Angew. Chem., Int. Ed. 2019, 58, 5592–5597.
2. J. Chromatogr. B Biomed. Appl. 2020, 1140, 121981.
3. Org. Proc. Res. Dev. 2019, 23, 2647–2654.
4. ACS Omega 2019, 4, 20564–20570.

Speakers

Zhala Tawfiq, Associate Technology Innovation Scientist, Ajinomoto Bio-Pharma Services, United States

Zhala Tawfiq is an Associate Scientist at Ajinomoto Bio-Pharma Services in San Diego, CA, focusing on the development and technical transfer of antibody-drug conjugates (ADCs) intended for clinical production, and continuous improvement of the global Aji Bio-Pharma Services business model and service capabilities.

Zhala holds a Bachelor of Science in Bioengineering, Biotechnology from the University of California, San Diego. Zhala has 10 years of experience in the pharmaceutical and CDMO industries, with the last 8 years leading and executing ADC process development activities. Zhala’s role at Ajinomoto Bio-Pharma Services is multi-faceted; she manages the ADC programs, serves as the liaison to parent company Ajinomoto on the development of novel technologies such as AJICAP, and supports business development as the ADC Subject Matter Expert.

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Yutaka Matsuda, Ph.D., ADC Researcher, Ajinomoto Co., Inc, Japan

Yutaka Matsuda is an ADC Researcher at Ajinomoto Co., Inc. in Japan. He focuses on various aspects of antibody-drug conjugates technology including novel site-specific conjugation methodology, process development and analytical assessments.

Yutaka holds two Ph.D. Degrees, a Ph.D. from Keio University and a Ph.D. from Tokyo University of Pharmacy and Life Sciences. In 2013, he began his scientific career with Ajinomoto Co. Inc. as a researcher. He then transferred to San Diego in 2018 to become an ADC researcher at Ajinomoto Bio-Pharma Services. In 2020, he returned back to Ajinomoto Co. Inc.

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