Cancer-specific plectin (CSP), a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, is a potentially promising target for the development of novel antibody-drug conjugates (ADC).

This conclusion is based on data presented by Lindsey Brinton, Ph.D., Principal Scientist and Head of Research, and Samantha Perez, Ph.D., Senior Scientist at ZielBio, at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida.[1]

CSP is involved in various cellular activities contributing to tumorigenesis, including cancer cell proliferation, adhesion, migration, invasion, and signal transduction. As a result,  plectin has emerged as a potent driver of malignancy in a wide range of cancers and correlates with poor prognosis and aggressive tumors, including pancreatic cancer and cholangiocarcinoma (bile duct cancer).[2]

In a Phase 0 imaging trial researchers at ZielBio evaluated a radio-labeled CSP-targeted peptide demonstrating that CSP is bioavailable and abundantly available on the surface of cancer cells (and not on cancer cells), validating CSP as a high-value drug target.

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Based on this outcome, and using a proprietary discovery approach, researchers at ZielBio developed ZB131, an antibody directed against CSP.  In preclinical studies, ZB131 demonstrated potent monotherapy efficacy in pancreatic, ovarian, and bile duct preclinical cancer models

Favorable pharmacokinetics
ZB131, which is currently being evaluated in a Phase 1/2 clinical trial (NCT05074472) across multiple solid tumors, demonstrated favorable pharmacokinetics and is rapidly internalized by CSP-expressing tumor cells in mouse models.

The available data also showed that ZB131 is an ideal target for an ADC: it is abundantly and selectively expressed in many indications, bioavailable, and its inhibition is predicted to synergize with FDA-approved payloads.

Orphan Drug Designation
In December 2022 the US Food and Drug Administration (FDA) granted Orphan Drug Designation for ZB131 for the treatment of pancreatic cancer, a rare solid-tumor cancer originating from the pancreas.

Earlier that same year, the FDA granted Orphan Drug Designation for ZB131 for the treatment of cholangiocarcinoma (bile duct cancer).

Antibody-drug conjugates
Over the last decades, major advances in payload and linker technology and the clinical adoption of antibody-drug conjugates (ADCs), allow for the identification of new targets that differentiate cancer cells from healthy cells across multiple tumor types.

Researchers at ZielBio development of two ZB131 based ADCs, ZB131-MMAE (ZB131 conjugated to monomethyl auristatin E) with drug-to-antibody ratio (DAR) of 3 – 4 and ZB131-DXd (ZB131 conjugated to deruxtecan)  with DAR of 7 – 8, respectively.

After binding, both ADCs rapidly and specifically internalized by CSP-positive cells resulting in drug payload release and enhancing cancer cell death compared to ZB131 alone. In addition, the researchers characterize cytotoxic activity in high and low CSP cell lines to evaluate ADC activity in relation to CSP abundance.

Overall outcome
In preclinical xenograft models, the ZB131 based antibody-drug conjugates enhanced tumor regression compared to controls at clinically relevant doses. Also, anti-huIgG staining revealed selective target engagement by ZB131-ADC.

Taken the pre-clinical data together, ZB131 based ADC demonstrate potent antitumor activity and support their further evaluation in a Phase 1 clinical trial.

“These findings underscore our enthusiasm for CSP as a therapeutic target and ZB131 as an excellent candidate for conjugation to payloads,” said Alan Bash, CEO of ZielBio.

“We are excited to share this data with the AACR community and are committed to exploring new avenues for deploying ZB131 against difficult-to-treat cancers,” Bash concluded.

Clinical trials
Phase 0 Biodistribution of Novel Imaging for Resectable Pancreatic Cancer – NCT01962909
A Phase 1/2, First-in-Human, Open Label, Dose Escalation Study Of A CSP Targeting Functional Antibody in Solid Tumors – NCT05074472

Reference
[1] Perez SM, Murphy BP, Heckert DB, Hall S, Colvin AL, Owens MF, Verfurth BR, Dimastromatteo J, He J, Adams RB, Kovtun Y, Brinton LT, Kelly KA. ZB131 antibody-drug conjugates induce potent antitumor activity [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 6299.
[2] Perez SM, Brinton LT, Kelly KA. Plectin in Cancer: From Biomarker to Therapeutic Target. Cells. 2021 Aug 30;10(9):2246. doi: 10.3390/cells10092246. PMID: 34571895; PMCID: PMC8469460.

Featured image: AACR annual meeting. Photo Courtesy: © 2018 – 2023 AACR/Todd Buchanan. Used with permission.

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