SUPERDIMERIC ANTIBODY-LIKE MOLECULE WITH DUAL FC DOMAINS PROVIDES POTENT B CELL DEPLETION WITH MINIMAL CYTOKINE INDUCTION VIA TARGETING OF CD19, CD20 AND FC GAMMA RECEPTORS
Bibliographic record
Abstract
PV265 / #821 Poster Topic: AS24 - SLE-Treatment Background/Purpose Potent tissue B cell depletion using CD19-targeting CAR-T cells or T cell engagers in patients with autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) has led to durable clinical responses in early clinical studies and the results suggest the potential to reset the autoreactive immune system for long-term disease remission. However, there are limits to the safety and accessibility of CD19-targeting CAR-T cells or T cell engagers across large patient populations. While antibodies targeting CD20 have provided significant responses in several autoimmune diseases, they do not deplete CD19 + /CD20 - autoantibody-secreting plasmablasts or pro-B cells in bone marrow. Antibodies targeting CD19 have shown efficacy in Neuromyelitis optica spectrum disorder (NMOSD) and IgG4-related disease in clinical trials. Deep and broad depletion of B cells by targeting both CD19 plus CD20 with an antibody-based approach may provide additional clinical benefits by restoring immune homeostasis in autoimmune diseases with low risk of cytokine-mediated adverse events. Methods Here we describe HB2198 generated using the GEM-DIMER™ platform. HB2198 was designed for bivalent target binding to both CD20 (Fab domains derived from rituximab) and CD19 (Fab domains derived from humanized version of FMC63, the parental antibody used to generate approved CD19-targeting CAR-T cell therapies) and importantly, contains 2 Fc domains both with amino acid variants S239D and I332E, further increasing Fc gamma receptor binding and immune effector functions. We assessed the B cell depletion, T and NK cell activation, and inflammatory cytokine release in response to HB2198 by flow cytometry, ELISA, and functional assays in vitro using cell lines and primary immune cells from healthy individuals and patients. Pharmacodynamic effects in vivo were evaluated in non-human primates. Results HB2198 exhibited enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) immune effector functions over conventional antibodies targeting CD19 or CD20. HB2198 potently depleted B cells from healthy human whole blood after overnight culture. Further, HB2198 depleted memory B cells from healthy and SLE patient PBMCs ex vivo . Importantly, little or no induction of inflammatory cytokines IFN-γ, IL-6, TNF-α, or IL-2 was detected in vitro and in vivo . These findings contrasted with dose-dependent, potent in vitro cytokine induction observed in the presence of a CD20-CD3 T cell engager. Infusion of HB2198 into cynomolgus monkeys led to >99% depletion of circulating B cells within 1-3 days and durable depletion of memory B cells with minimal inflammatory cytokine response in vivo . Conclusions HB2198 demonstrated potent B cell depletion in vitro and long-term reduction in memory B cell depletion in vivo , suggesting the potential for broad and deep depletion of autoantibody producing cells. Importantly, minimal induction of proinflammatory cytokines was observed in vitro and in vivo . These data support the advancement of HB2198 in autoimmune indications where depletion of CD19 + and/or CD20 + cells would provide clinical benefit.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".