Friday, April 19, 2019

AstraZeneca reviews the ADC Therapeutic Window


A great new paper from the Team at AstraZeneca about the problem of small therapeutic window in ADC therapies

https://doi.org/10.1158/1078-0432.CCR-19-0272

Out of the 55 traditional ADCs whose clinical development has been halted, an estimated 23 were due to poor therapeutic index.

Dose toxicity resulted in skipped doses, dose reductions, or complete discontinuation.  Many of which occured prior to reached to maximum efficacious dose.

The reported toxicity in many cases matches that of the warhead toxicity.  This indicates that despite the "targeted" nature of ADCs, the systemic toxicity is still being caused by the release of the warhead into non-tumor cells.

The 4 approved ADCs have demonstrated clear clinical benefits, and this is likely to the conjugate allowing a slightly higher dosing than a systemic administration of "naked" chemotherapeutics.

Some of the emerging trends to overcome the limited therapeutic window include modified clinical dosing schedule, biodistribution studies, and optimized patient selection with biomarkers.

Optimizing patient populations is particularly intersting if the focus for selection shifts from tumor expression levels to warhead mechanism of action.  For example, patient populations prone to DNA damage responses could possibly respond more strongly to DNA repair inhibitors such as PBDs.

The authors also identify the potential for improved real-time biomarkers to monitor the effect of an ADC therapeutic treatment.  This could shed light on bystander effects, tumor burden, and patient mutational profiles.  In addition, a more thorough biomarker profile could be implemented to understand the effects of combination therapies which are becoming increasingly more popular.

Similar work has been done by BioMed Valley Discoveries regarding a CD276 tumor vasculature model where they demonstrated significant apoptosis when using a PBD linked antibody, and no effect when using vcMMAE.
The authors state that these data explain why a previous study into glioblastoma multiform was unsuccessful

Eradication of Tumors through simultaneous ablation of CD276 positive tumors and vasculature
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458750/

So my question is:
1) Why have industry expectations for massive therapeutic windows been so far off of the mark?
2) Matching payload with cancer, mechanism seems logical. Why is this just being brought up as a topic now, 20 years into the ADC lifecycle?


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