Characterization of anti-drug antibody responses to the T-cell engaging bispecific antibody cibisatamab to understand the impact on exposure.

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, 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 for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the 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 and allows a correlation between ADA response and loss of exposure. Therefore, the described 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.

On peace and its logic.

Glowacki argues that the human capacity for peace emerged 100,000 years ago, and that the logic of peace is such that the traits and technologies that enable peace are the same that are used to wage war. In my commentary I raise some concerns about these points as well as about Glowacki's understanding of peace.

Sidestepping the semantics of "consciousness"

Block explains the conflation of phenomenal consciousness and access consciousness by appeal to the ambiguity of the term "consciousness." However, the nature of ambiguity is not at all clear, and the thesis that "consciousness" is ambiguous between phenomenal consciousness and access consciousness is far from obvious. Moreover, the conflation can be explained without supposing that the term is ambiguous. Block's argument can thus be strengthened by avoiding controversial issues in the semantics of "consciousness."