ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1
Simon-Peter Williams1, Annie Ogasawara1, Jeff N Tinianow1
1Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA, 94080, USA.
Abstract:
The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.1). Three aspects of ADC biology were measured and compared: efficacy was measured in tumor growth inhibition studies; target expression was measured by immunohistochemistry and flow cytometry; and tumor antibody uptake was measured with 111In-mAbs and gamma counting or with 89Zr-immunoPET. Within each model, the mAb with the highest tumor uptake showed the greatest potency as an ADC. Sensitivity between models varied, with the LuCaP77 model showing weak efficacy despite high target expression and high antibody uptake. Ex vivo analysis confirmed the in vivo results, showing a correlation between expression, uptake and ADC efficacy. We conclude that 89Zr-immunoPET data can demonstrate which ADC candidates achieve the penetration, binding, and internalization necessary for efficacy in tumors sensitive to the toxic payload.
Insights
Antibody-drug conjugates (ADCs) efficacy in solid tumors is hard to monitor. 89Zr-immunoPET imaging can confirm ADC penetration, binding, and internalization, correlating with therapeutic efficacy in prostate cancer models.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- Antibody-drug conjugates (ADCs) are promising cancer therapeutics, but their in vivo performance is challenging to assess.
- Understanding ADC penetration, binding, and internalization is crucial for predicting clinical efficacy.
Purpose of the Study:
- To evaluate the utility of 89Zr-immunoPET for monitoring ADC behavior in vivo.
- To correlate ADC tumor uptake with therapeutic efficacy in metastatic castration-resistant prostate cancer models.
Main Methods:
- Studied monomethyl auristatin E (MMAE) ADCs targeting TENB2 and STEAP1 in four patient-derived prostate cancer models.
- Assessed ADC efficacy via tumor growth inhibition studies.
- Measured target expression (immunohistochemistry, flow cytometry) and antibody uptake (111In-mAbs, 89Zr-immunoPET, gamma counting).
Main Results:
- Higher tumor antibody uptake correlated with greater ADC potency within each model.
- Significant variability in model sensitivity observed; LuCaP77 showed weak efficacy despite high uptake and target expression.
- Ex vivo analyses confirmed in vivo findings, demonstrating a link between target expression, uptake, and ADC efficacy.
Conclusions:
- 89Zr-immunoPET imaging is a valuable tool for assessing critical ADC biological processes in vivo.
- This imaging modality can identify ADC candidates with sufficient tumor penetration, binding, and internalization for efficacy.
- Results highlight the importance of correlating imaging biomarkers with therapeutic outcomes in ADC development.
More Related Videos
10:19Tracking Bispecific Antibody-Induced T Cell Trafficking Using Luciferase-Transduced Human T Cells
Published on: May 12, 2023
11:58Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting
Published on: March 8, 2018