# Precision immunotherapies targeting the 9G4 idiotype in lupus erythematosus

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,688

## Abstract

PROJECT SUMMARY/ABSTRACT
B cells are immunopathogenic drivers of systemic lupus erythematosus (SLE), an autoimmune disease
characterized by a large repertoire of autoantibodies targeting self-protein and nucleic acids. While B cell-
directed T-cell therapies have curative potential in the treatment of B-cell cancers and can achieve complete
disease remission in refractory lupus, therapies that deplete all B cells are associated with excess morbidity and
mortality from infection, precluding their use beyond life-threatening disease. Precision therapies that selectively
target autoreactive B cells that drive SLE, while preserving normal B cell populations, are therefore critically
needed, but targeting the plethora of autoreactive B cells in SLE poses practical challenges. The autoreactive B
cell compartment in SLE is uniquely characterized by the expansion B cells bearing B-cell receptors (BCRs)
using the variable heavy-chain allele VH4-34, which encodes the idiotype 9G4 (9G4id B cells). 9G4id B cells
contribute 10–45% of total IgG in patients with active SLE, including antibodies against canonical lupus
autoantigens. 9G4id B cells are therefore promising targets for the selective depletion of the autoreactive B cell
pool, opening opportunities to treat lupus without increasing the risk of infection. Here, we hypothesize that
autologous T cells can be redirected to selectively bind and kill 9G4id B cells expanded in SLE. To achieve this,
we will develop 9G4id-targeted bispecific T cell-engaging antibodies designed to cross-link 9G4id B cells with any
T cell, thereby inducing killing of target B cells. In this proposal, we will graft single chain variable fragments of
an anti-9G4id-specific antibody and those of well-characterized CD3-specific antibodies (i.e., OKT3, UCHT1v9)
into different therapeutic bispecific formats (i.e., BiTE and scDb). The efficacy and specificity of anti-9G4
bispecific antibodies to selectively bind and deplete 9G4id B cells will be established in fully-controlled in vitro
model systems using engineered human B cell lines expressing 9G4id autoreactive BCRs cloned from patients
with SLE, human B cell lines expressing monoclonal non-9G4id BCRs, and using autologous B cells and T cells
isolated from the peripheral blood of patients with SLE. The final goal of this work is to lay the foundation for
evaluating these precision immunotherapies as a novel therapeutic strategy in SLE.

## Key facts

- **NIH application ID:** 10772166
- **Project number:** 5R21AI176764-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Felipe Andrade
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2023-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772166

## Citation

> US National Institutes of Health, RePORTER application 10772166, Precision immunotherapies targeting the 9G4 idiotype in lupus erythematosus (5R21AI176764-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772166. Licensed CC0.

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