Background/Purpose: A common reason for clinical development failure of biologic medicines is immunogenicity. Immunogenicity is traditionally measured by detecting neutralizing (NAb) anti-drug antibodies (ADA) in plasma or serum (humoral response). However, the onset of a sustained immunogenic response starts at the cellular level with the activation of T cells and maturation of naïve B cells into plasma cells, the endogenous source for ADA.In addition to the conventional measurement of humoral response, we used an ex vivo comparative immunogenicity assessment (EVCIA), an innovative assay to measure immunogenicity at the cellular level, to compare the immunogenicity of proposed biosimilar AVT02 and Humira® (reference adalimumab). The EVICA assay was implemented in study AVT02-GL-302, a clinical study to support the demonstration of interchangeability between AVT02 and reference adalimumab (ClinicalTrials.gov Identifier: NCT04453137).

Methods: Following a 12-week open label lead-in period when all participants received reference adalimumab, participants with Psoriasis Area Severity Index(PASI)75 response were randomized 1:1 to receive either AVT02 alternating with reference adalimumab (switching arm) or reference adalimumab (non-switching arm). Peripheral blood mononuclear cells (PBMCs) of 28 participants overall were collected and cryopreserved before treatment (pre-dose / Week 1), at the start of the switching period (Week 12), after a single switch between reference adalimumab and AVT02 (Week 16) and after repeated switches between reference adalimumab and AVT02 (Week 28).Frozen PBMC’s were thawed and re-exposed to one of medium alone, reference adalimumab, AVT02, keyhole limpet hemocyanin (KLH), reference adalimumab + KLH or AVT02 + KLH. After 24h, cells were analyzed for cytokine release (IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, MCP-1). After 6 days, samples were analyzed for T cell proliferation. Analysis was performed on samples from 10 participants from each arm.

Results: Cytokine release was highly similar between AVT02 and reference adalimumab, in all samples measured at all time points and in PBMCs from participants in both the switching and non-switching arms. T cell proliferation was likewise similar.

Conclusion: Immune response was not increased in samples from participants in the switching arm compared to the non-switching arm as measured by EVCIA. This novel assay provides a unique evaluation of both qualitative and quantitative changes in the cellular immunogenic response induced by switching conditions in vivo. Initial cellular response could be a valuable additional outcome to predict overall immune response to biologic medicines, currently typically measured by the later development of ADAs and NAbs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ex-vivo-comparative-immunogenicity-assessment-evcia-to-determine-relative-immunogenicity-in-chronic-plaque-psoriasis-in-participants-receiving-humira-or-undergoing-repeated-switches-between-hu/