Characterization of Anti-Drug Antibody Responses to Cibisatamab
Practical Solutions and Value
An appropriately designed pharmacokinetic (PK) assay sensitive for anti-drug antibody (ADA) impact on exposure is an alternative strategy to understand the neutralizing potential of ADAs.
The PK assay of cibisatamab, a T-cell-engaging bispecific antibody, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically.
In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays can correlate the ADA response with cibisatamab exposure. Advanced ADA characterization has been performed to understand the neutralizing potential of patient-derived ADAs on drug activity.
Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. Relevant patient ADA binding features were identified and compared with specific monoclonal anti-ID antibody-positive controls.
Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs, allowing a correlation between ADA response and loss of exposure.
This study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.
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