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With 4 approved agents, antibody-drug conjugates or ADC have shown to be a very promising class of therapeutics.

While the concept of ADCs is not new, effectively linking a small molecule drug to a monoclonal antibody to increase the therapeutic index (TI) of the attached chemotherapeutic agent allowing a more selective delivery of cytotoxic agents to tumor cells while, at the same time, limiting exposure to healthy, normal, cells, in not  a simple undertaking. [1]

Dose limiting toxicities
And despite the fact that antibodies targeting antigens abundantly and/or exclusively expressed on cancer cells (i.e., target cells), dose limiting toxicities (DLTs) in normal cells/tissues are frequently reported even at suboptimal therapeutic doses.

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While advancement of ADC technology have helped to optimize all three key components of an antibody-drug conjugate (i.e., mAb, linker, and payload), dose limiting toxicities remain a key challenge.

While the majority of DLTs are considered to be target-independent, the underlying mechanisms of ADC related toxicity in normal cells/tissues are not clearly understood.

Further, linker-drug instability contributing to the premature release of cytotoxic drug (payload) in circulation, uptake/trafficking of intact ADCs by both receptor-dependent (FcγRs, FcRn and C-type lectin receptors), and-independent (non-specific endocytosis) mechanisms may contribute to off-target toxicity in normal cells.

Understanding underlying mechanisms
In an article published in the April 24, 2019 edition of Pharmacology & Therapeutics, the authors review potential mechanisms of target-independent ADC uptake and toxicity in normal cells.  They also discuss components of ADCs which may influence these mechanisms. [1]

The authors provide a deeper understanding of the underlying mechanisms of ADC off-target toxicity. Their research will prove to be helpful in improving the overall therapeutic index of the next generation of Antibody-drug Conjugates.

Reference
[1] Mahalingaiah PK, Ciurlionis R, Durbin KR, Yeager RL, Philip BK, Bawa B, Mantena SR, Enright BP, Liguori MJ, Van Vleet TR. Potential Mechanisms of Target-Independent Uptake and Toxicity of Antibody-Drug Conjugates. Pharmacol Ther. 2019 Apr 24. pii: S0163-7258(19)30071-3. doi: 10.1016/j.pharmthera.2019.04.008.[Pubmed][Article]