SGN-CD228A Is an Investigational CD228-Directed Antibody-Drug Conjugate with Potent Antitumor Activity across a Wide Spectrum of Preclinical Solid Tumor Models

Sep 24, 2026

SGN-CD228A is an investigational antibody-drug conjugate directed to melanotransferrin (CD228), a melanoma cell-surface protein. It pairs a humanized antibody (hL49) with high specificity for CD228 and stable conjugation to eight monomethyl auristatin E (MMAE) molecules via a novel glucuronide linker. Comprehensive IHC and RNA sequencing aligned low CD228 expression in normal tissues with high expression in melanoma, NSCLC, TNBC, colorectal, and pancreatic cancers. Internalization and CD228-dependent MMAE sensitivity drove cytotoxicity, and the glucuronide linker enhanced in vitro MMAE retention and in vivo antitumor activity across heterogeneous models. CD228 expression mattered in vivo but did not correlate uniformly, suggesting additional ADC determinants. A Phase I trial evaluates SGN-CD228A in advanced solid tumors (NCT04042480).

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Abstract

Introduction

Antibody–drug conjugates (ADCs) overview

MCT FIRST DISCLOSURES SGN-CD228A Is an Investigational CD228-Directed Antibody–Drug Conjugate with Potent Antitumor Activity across a Wide Spectrum of Preclinical Solid Tumor Models Rebecca Mazahreh, Marsha L. Mason, John J. Gosink, Devra J. Olson, Robert Thurman, Christopher Hale, Lori Westendorf, Thomas A. Pires, Christopher I. Leiske, Markus Carlson, LiemT. Nguyen, Julia H. Cochran, Nicole M. Okeley, Roma Yumul, Steven Jin, Ivan J. Stone, Disha Sahetya, Albina Nesterova, Sean Allred, Kelly M. Hensley, Rachael Hu, Robert Lawrence, Timothy S. Lewis, and Sharsti Sandall |
ABSTRACT | | | --- | --- | | SGN-CD228A is an investigational antibody–drug conjugate (ADC) directed to melanotransferrin (CD228, MELTF, MFI2, p97), a cell-surface protein ﬁrst identiﬁed in melanoma. SGNCD228A consists of a humanized antibody, hL49, with high speciﬁcity and afﬁnity for CD228that is stably conjugated to8molecules of the clinically validated microtubule-disrupting agent monomethyl auristatin E (MMAE) via a novel glucuronide linker. We performed comprehensive IHC studies, which corroborated published RNA sequencing data and conﬁrmed low CD228 expression in normal tissues and high expression in several cancers, including melanoma, squamous non–small cell lung cancer (NSCLC), triplenegative breast cancer (TNBC), colorectal cancer, and pancreatic cancer. SGN-CD228A was efﬁciently internalized in various tumor cell types, and its cytotoxic activity was dependent on CD228 expression and internalization and intrinsic sensitivity to the MMAE payload. Compared with the valine-citrulline dipeptide linker, the novel glucuronide linker increased the cellular retention of MMAE in vitro and conferred improved antitumor activity against melanoma cell lines in vitro and in vivo. In addition, SGN-CD228A was active across melanoma, TNBC, and NSCLC cell line-and patient-derived xenograft models with heterogeneous antigen expression. In vivo, CD228 expression was important for | response to SGN-CD228A but was not well correlated across all tumor types, suggesting that other factors associated with ADC activity are important. Overall, SGN-CD228A is a CD228-directed, investigational ADC that employs innovative technology and has compelling preclinical antitumor activity. SGN-CD228A is investigated in a Phase I clinical trial (NCT04042480) in patients with advanced solid tumors.
| | Introduction
Melanotransferrin (CD228, MELTF, MFI2, p97) is a glycophosphatidylinositol (GPI)-anchored membrane protein ﬁrst described asa melanoma-speciﬁc antigen (1) . CD228 shares high homology with other members of the transferrin family of iron-binding proteins and has 37% to 39% amino acid identity with human serum transferrin, lactoferrin, and ovotransferrin (2, 3) . Two forms of CD228 have been
Seagen Inc., Bothell, Washington.
R. Mazahreh and M. L. Mason contributed equally to this article.
Corresponding Author: Sharsti Sandall, Seagen Inc., 21823 30th Drive SE,
Bothell, WA 98021 . E-mail: [SSandall@seagen.com](SSandall@seagen.com)
[Mol Cancer Ther 2023](Mol Cancer Ther 2023);[22:421](22:421)–[34](34)
[doi:](doi: 10.1158/1535-7163.MCT-22-0401)[ 10.1158/1535-7163.MCT-22-0401](doi: 10.1158/1535-7163.MCT-22-0401)
This open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license.
􀀁2023The Authors;Published by the American Association for Cancer Research | reported: a GPI-anchored variant and a shorter secreted variant that lacks the C-terminal GPI anchor and can be transported across the blood-brain barrier (4) . CD228 is an oncofetal antigen with demonstrated expression in fetal colon and umbilical cord tissue and high expression in multiple solid tumors, such as melanoma, non–small lung cancer (NSCLC), triple-negative breast cancer (TNBC), colorectal, and pancreatic cancer (refs. 3, 5; Fig. 1) . Importantly, CD228 has shown highly restricted low-level exp

FAQs

What is SGN-CD228A and what target does it use?

SGN-CD228A is an investigational antibody-drug conjugate that is directed to melanotransferrin (CD228), a cell-surface protein identified in melanoma.

How is the drug payload delivered in SGN-CD228A?

SGN-CD228A uses a humanized hL49 antibody stably conjugated to MMAE through a novel glucuronide linker, enabling release of the cytotoxic payload after linker cleavage.

What preclinical evidence supports SGN-CD228A activity?

Preclinical IHC and RNA sequencing showed low CD228 in normal tissues and high expression across multiple cancers. SGN-CD228A was internalized in tumor cells, and its cytotoxicity depended on CD228 expression, internalization, and intrinsic sensitivity to MMAE, with improved antitumor activity versus a valine-citrulline linker.

Sep 24, 2026

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