Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation

Fichter, Marie; Richter, Gregor; Bepperling, Alexander; Wassmann, Paul

doi:10.3390/pharmaceutics14061254

Cited by 2 publications

(1 citation statement)

References 47 publications

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“…Multiple technical challenges prevent assessment of such compositions at nominal concentrations with available physicochemical tools. The composition of IOF as matrix with high content of various biomolecules poses additional complexity for the analysis ( 25 , 26 ). To overcome these limitations, brolucizumab and mono- and polyclonal anti-brolucizumab antibodies, serving as an ADA surrogate, were tested at the relevant ratios, but at higher absolute concentrations compared with the physiological conditions.…”

Section: Resultsmentioning

confidence: 99%

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab

et al. 2023

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Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.

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Section: Resultsmentioning

confidence: 99%

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab

et al. 2023

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Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection

Petro,

Hooper,

Peace

et al. 2024

Sci. Transl. Med.

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Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein–directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti–spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2–infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.

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Pre-Clinical In-Vitro Studies on Parameters Governing Immune Complex Formation

Cited by 2 publications

References 47 publications

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab

A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab

Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection

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