Abstract 2658: ZW251, a novel glypican-3-targeting antibody drug conjugate bearing a topoisomerase 1 inhibitor payload
Bibliographic record
Abstract
Abstract Background: Glypican-3 (GPC3) is a cell-surface oncofetal glycoprotein frequently expressed in hepatocellular carcinoma (HCC) with minimal presence in normal adult tissues. ZW251 is an antibody-drug conjugate (ADC) targeting human GPC3, composed of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor, ZD06519, via a maleimide anchor and a glycyl glycyl phenylalanyl glycine (GGFG)-aminomethyl (AM) cleavable linker. Materials and Methods: Extensive functional characterization was performed to assess the mechanism of action and therapeutic potential of the ZW251 ADC. Antibody binding to human and cynomolgus monkey GPC3 was assessed by surface plasmon resonance and flow cytometry. A screen of off-target binding and target specificity was conducted using a membrane proteome array. ZW251 antibody internalization in GPC3-expressing tumor cell lines was assessed by flow cytometry. In vitro ADC cytotoxicity against tumor monolayers and spheroids was assessed in a panel of HCC cell lines. Tumor cell co-culture assays were also performed to assess bystander-mediated cell killing by ZW251. The pharmacokinetic (PK) profile of the ZW251 antibody was assessed in Tg32 mice expressing human FcRn. Anti-tumor activity of ZW251 was investigated in a large panel of cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models representing a range of GPC3 expression. Results: The ZW251 antibody backbone demonstrated nanomolar binding affinity to both human and cynomolgus monkey GPC3, and strong binding to target-expressing cancer cell lines. Rapid internalization of ZW251 antibody was observed in GPC3-expressing HCC cell lines. ZW251 exhibited potent and target-specific cytotoxicity in a panel of HCC cells cultured either in monolayer or as 3D spheroids. ZW251 showed effective bystander-mediated killing of GPC3 negative cancer cells when in co-culture with GPC3 positive cancer cells. The ZW251 antibody demonstrated a favorable PK profile in Tg32 mice. A single administration of ZW251 resulted in robust tumor growth inhibition of a large panel of CDX and PDX models representing a range of GPC3-expression. Overall, these results support the potential of ZW251 as a novel therapeutic agent against GPC3-bearing cancers. Citation Format: Laurence Madera, Andrea Hernández Rojas, Raffaele Colombo, Alex Wu, Chayne L. Piscitelli, Dunja Urosev, Allysha Bissessur, Chi Wing Cheng, Renee Duan, Catrina Kim, Kevin Yin, Vincent Fung, Kaylee Wu, Winnie Cheung, Diego A. Alonzo, Mark E. Petersen, Stuart D. Barnscher, Jamie R. Rich. ZW251, a novel glypican-3-targeting antibody drug conjugate bearing a topoisomerase 1 inhibitor payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2658.
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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) | 0.000 | 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) | 0.001 | 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".