Using Radiolabeling Techniques to Improve ADC Pharmacokinetic Studies

While several payloads of antibody-drug conjugate (ADC) have been marketed, challenges persist in accurately assessing tissue distribution, in vivo metabolism, and ADC excretion due to factors such as low systemic exposure of payloads, severe matrix interference, and the unpredictability of cleavage products of non-cleavable ADCs.

How to Select Ideal Radioisotopes for the Radiolabeled Synthesis of Payloads and Antibodies?

Payloads are usually radiolabeled with low-energy radioisotopes such as ¹⁴C or ³H, however, ³H labeling is more difficult and costly. Consequently, while meeting the detection requirements, it is recommended to choose ¹⁴C to label payloads. Furthermore, antibodies are usually radiolabeled with high-energy radioisotopes such as ¹²⁵I or ⁸⁹Zr. ¹²⁵I is the most common choice for labeling due to its ready availability, simple labeling process, and its minimal impact on antibody activity.

How to Select ADC Drugs with Optimal ADC DAR in the Discovery and Development Phase?

In the development phase, highly sensitive radiolabeling technology allows the accurate determination of ADC PK behavior in vivo. In addition, labeling naked antibodies, ADC antibodies, and payloads separately, as well as comparing the difference in the in vivo behavior of different radiolabeling locations and conjugation methods could facilitate the selection of optimal ADC candidates at the earliest possible stages.

Why is Adopting Radiolabeling Techniques to Profile the In Vivo Characteristics of the ADC Drug Recommended？

It is important to highlight that quantitative whole-body autoradiography (QWBA) can provide average concentrations within whole tissues and can differentiate concentration differences among regions within the tissue and then quantify tissues by region. Compared with conventional harvesting methods, QWBA offers incomparable advantages in assessing dose-response relationships between the ADC distribution depth in tumor tissues and drug efficacy.

In animal tests, plasma concentration and tissue distribution results are essential for ADC efficacy and safety assessments, and concentrations of ADC, total antibody, and unconjugated payloads should be assessed. It is recommended to adopt radiolabeling techniques to track the tissue distribution behavior in vivo and to examine whether the tissue distribution characteristics of payloads and antibodies align after labeling them separately.

If you want to learn more details about the use of radiolabeling techniques for ADC PK studies, please read the article now.

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