# The role of large immune complexes in anti-drug antibody development: a case study of anti-SARS-CoV-2 antibody therapeutics and co-administered mRNA vaccine

## TL;DR

This study shows that mRNA vaccines may increase immune responses to certain antibody treatments by forming large immune complexes.

## Contribution

The study identifies large immune complexes as a novel mechanism linking mRNA vaccination to anti-drug antibody formation.

## Key findings

- ADA incidence for CAS+IMD was over 3-fold higher in vaccinated participants.
- Large immune complexes (1.6-4 MDa) formed between CAS+IMD and spike trimer.
- Increased ADA was specific to mRNA vaccines, not observed with other vaccine types.

## Abstract

The administration of therapeutic proteins may induce an anti-drug antibody (ADA) response which may impact pharmacokinetics, safety or efficacy. Numerous factors contribute to ADA development, such as patient population, drug sequence, formulation impurities, as well as drug dose and frequency. Here we report data from a natural experiment where ADA incidence for monoclonal antibodies (mAbs) casirivimab (CAS) and imdevimab (IMD), targeting the SARS-CoV-2 spike protein, was more than 3-fold higher in COVID-19 vaccinated participants compared to unvaccinated. Although ADA incidence to the mAbs was elevated in vaccinated participants, there was no increase in the strength or magnitude of the ADA response, despite these participants developing robust immunogenicity directed against the COVID-19 vaccine. In vitro studies using sedimentation velocity analytical ultracentrifugation demonstrated large complexes (ranging from 1.6 to 4 MDa) being formed between CAS+IMD and recombinant spike trimer. In addition, the substantially increased immunogenicity to CAS+IMD was only observed in participants receiving mRNA-LNP-based products, likely due to higher expression of spike protein compared to adenovirus-based products. No increase in ADA was observed in COVID-19 vaccinated participants receiving mAbs to unrelated targets, suggesting COVID-19 vaccination was not a general adjuvant. Taken together, these data suggest in participants vaccinated with mRNA-LNP-based products, the formation of large mAb-target immune complexes likely results in greater surveillance by immune cells and increased ADA development to mAbs against the same target.