ZW38, a bispecific CD3 x CD19 azymetric antibody to deplete human leukemic B cells by the “controlled” activation of T cells.
Bibliographic record
Abstract
e14019 Background: Redirected T cell cytotoxicity (RTCC) has emerged as a promising mechanism for cancer treatments and relies on the co-engagement of tumor antigens and T cells, which can be achieved by the use of bi-specific antibodies. While efficacious, drug classes (like bi-specific T-cell engagers) that redirect the immune system are associated with severe cytokine release syndrome and neurological toxicities. ZW38 is an efficacious bi-specific CD3 x CD19 antibody engineered to confer T cell cytotoxicity with controlled T cell activation for maximal B cell depletion while retaining favorable antibody-like PK and CMC properties. Methods: A bi-specific CD3 x CD19 T cell engager, ZW38, was engineered based on our proprietary Azymetric IgG1-based antibody scaffold. ZW38 was evaluated for its ability to deplete B cells, stimulate T cell proliferation, and promote cytokine release. Results: ZW38 binds to CD3+ and CD19+ cells with nM affinity, and efficiently forms cytolytic immune synapses between human T and B cells. ZW38 effectively depletes human CD19+ lymphoma cells and autologous B cells from ex vivo PBMC and human whole blood cultures and robustly depletes autologous B cells in CLL, MCL, and NHL patient-derived whole blood. In vivo activity of ZW38 was assessed in NSG mice engrafted with IL-2 activated human PBMC and human B-ALL cells. ZW38 induced near complete depletion of leukemic ALL B cells in peripheral blood and secondary lymphoid organs. ZW38’s activity is strictly target dependent as it has been demonstrated to spare CD19- erythroleukemia cells even in the presence of IL-2 stimulated T cells. Furthermore, low levels of T cell proliferation and cytokine release accompanied ZW38-mediated killing, which may translate into an improved therapeutic index. ZW38’s Fc domain has been engineered to knockout Fc-mediated effector functions while retaining binding to FcRn to maintain antibody-like serum half-life and a favorable dosing schedule. Conclusions: ZW38’s efficacy, toxicity profile, PK characteristics, and manufacturability position it as a promising potential therapeutic to treat CD19+ B cell malignancies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".