Aim

To analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor.

Methods

We review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures.

Results

In some cases, the failures are unavoidable due to the lack of adequate science, but in others, we characterize the causes of such failures and recommend how such failures may have been avoided.

Conclusion

By learning from previous mistakes and adhering to the principles and recommendations provided, it is possible to avoid these common pitfalls, increasing the likelihood of success in phase III clinical trials, and thus securing regulatory approval.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy^1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ_c) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ_c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.