Antidrug Antibodies Against Immune Checkpoint Blockers: Impairment of Drug Efficacy or Indication of Immune Activation?

Abstract

The generation of antibodies following exposure to therapeutic drugs has been widely studied, however in oncology, data in relation to their clinical relevance are limited. Antidrug antibodies (ADAs) can cause a decrease in the amount of drug available, resulting in some cases in decreased antitumor activity and a consequent impact on clinical outcomes. Several immunologic factors can influence the development of ADAs, and in addition, the sensitivity of the different testing methods used in different studies can vary, representing an additional potential confounding factor. The reported frequency of ADA-positive patients following treatment with immune checkpoint inhibitors varies from as low as 1.5% for pembrolizumab to 54% for atezolizumab. This latter drug is the only immune checkpoint inhibitor to have undergone an expanded analysis of the clinical implications of ADAs, but with discordant results. Given that immune checkpoint inhibitors can modify the immune response and potentially impact ADA formation, data from published as well as prospective trials need to be evaluated for a better understanding of the clinical implications of ADAs in this setting.

Anti‐PD1 versus anti‐PD‐L1 immunotherapy in first‐line therapy for advanced non‐small cell lung cancer: A systematic review and meta‐analysis

“…Together, these two results might imply that anti‐PD1 antibodies induce stronger antitumoral therapy 20 . These differences might also derive from heterogeneous immunogenicity of the antibodies themselves, eliciting neutralizing antibodies against the anti‐PD1 or ant‐PD‐L1 antibodies that could dampen their activity to different extents 21 …”

Principal stratum strategy: Potential role in drug development

“…Enrico et al 22 give an overview of the issue of ADAs in the class of immune checkpoint blockers and re‐analyze data of drug trials, by ADA status. They define ADA‐positivity by “patient has ever been ADA+ during the observation period.” However, as discussed in the previous section, naive analyses defining groups through a post‐randomization event will lead to (i) the comparison of non‐comparable population on the treatment groups and (ii) in this example also to immortal bias (see also, e.g., Anderson et al, 19 , 23 Anderson, 24 Walraven et al 25 and the discussion later in Section 4.7).…”

Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

“…The variation in ICIs is potentially no less important than that of the combination partner. There appears to be a difference in outcomes for various PD-1 pathway ICIs despite being trialed in the same settings [107]. One possible explanation is that different ICIs may stimulate the production of antidrug antibodies (ADA) by the humoral immune system to a different degree.…”

“…One possible explanation is that different ICIs may stimulate the production of antidrug antibodies (ADA) by the humoral immune system to a different degree. To date, the ICI with the highest incidence of, and most well-studied ADA phenomena is atezolizumab, which has been quoted to have up to 54.1% of patients developing ADAs in selected analysis [107]. The incidence of, and indeed implications of ADA, is not conclusive-some studies suggest that ADAs are neutralizing and thus reduce efficacies of ICIs, others suggest that they either have no impact or even positive relationships with survival outcomes [107][108][109].…”