Abstract
PurposeAntibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs’ function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells.MethodsThe ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay.ResultsAggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions.ConclusionsThese results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity.
Highlights
Supplementary Information The online version contains supplementary material available at https://doi.org/10. 1007/s11095-0 21-0 3158-x.Antibody-drug conjugates (ADCs), which are monoclonal antibodies conjugated with highly toxic small molecules via linkers, are one of the fastest growing classes of generation mAbs
Though the profiles of the size distribution of ADC aggregates differed between the induction methods, the aggregates induced by the same type of stress showed a similar profile regardless of whether they were mAbs or ADCs
The mechanism of off-target toxicity of ADCs is considered to be the internalization of ADCs and/or the free payload released from ADCs into non-target cells
Summary
Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic small molecules (payloads) via linkers, are one of the fastest growing classes of generation mAbs. ADCs combine the advantages of the target-specificity of mAbs with the high tumor killing efficacy of payloads. ADCs are transported to the cells expressing their target antigens in accordance with the function of mAbs, and the ADCs are internalized and subsequently release the payloads to kill the target cells. It is expected that ADCs will reduce the systemic exposure of cytotoxic small molecules while providing a wider therapeutic window compared. The development and commercial application of ADCs have been progressing in recent years. Six of ten FDA-approved ADCs were approved since the start of 2019, and 85 candidates are at the clinical development stage in various countries [1]
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