Targeting Solid Tumors with SGN-CD228A: A Promising Anti-CD228 Antibody-Drug Conjugate

Melanotransferrin, also known as CD228, is a glycoprotein that is part of the transferrin family and is linked to iron-binding. Initially identified as an oncofetal protein, it is notably present on melanoma cells. Analysis from The Cancer Genome Atlas indicates that CD228 is expressed in a variety of carcinomas and has been identified as a potential marker for invasive colorectal cancer.

In our research, we used immunohistochemistry to examine CD228's protein expression and to study the antitumor effects of SGN-CD228A, a CD228-targeted antibody-drug conjugate (ADC). We discovered that CD228 is not only overexpressed in melanoma but also in other types of cancer, including mesothelioma, non-small cell lung cancer, breast, colorectal, and pancreatic carcinomas.

We selected a leading monoclonal antibody (mAb) for human CD228, based on its binding and internalization properties, as well as its cytotoxic activity when used as an ADC. SGN-CD228A is a humanized anti-CD228 mAb conjugated with eight molecules of MMAE, a cytotoxic drug that disrupts microtubules. The conjugation is done through a β-glucuronidase-cleavable linker that includes a PEG side chain and a self-stabilizing maleimide, which enhances homogeneity and reduces plasma clearance, leading to increased antitumor activity.

Our evaluation of the drug linker revealed that changing from a di-peptide to a β-glucuronidase linker significantly improved the cytotoxicity of MMAE, possibly due to the unique trafficking and recycling mechanism of CD228. Among 50 carcinoma cell lines tested, 41 showed high CD228 receptor expression, with 60% having EC50 values less than 10ng/ml and 30% having EC50 values between 10-100ng/ml when treated with SGN-CD228A.

In vivo testing in melanoma and non-small cell lung cancer (NSCLC) xenograft and patient-derived xenograft (PDX) models demonstrated the potent antitumor activity of SGN-CD228A. In melanoma models, a single dose of 0.33 mg/kg delayed tumor growth, while 1.0 mg/kg resulted in durable complete responses in a significant number of cases. In the squamous NSCLC model, a single dose of 1.0 mg/kg led to durable responses in all tested cases. Similar results were observed in NSCLC PDX models, with tumor delay or durable responses achieved at 1.0 mg/kg and complete responses at 3.0 mg/kg.

Furthermore, in a clinical trial involving a mouse triple-negative breast cancer (TNBC) PDX model, SGN-CD228A demonstrated durable complete responses even in PDX models with low CD228 expression. Overall, our findings indicate that CD228 is a promising target for carcinomas and that the novel ADC, SGN-CD228A, exhibits significant antitumor efficacy both in vitro and in vivo.

Reference: Sharsti L. Sandall et al. SGN-CD228A: A novel humanized anti-CD228 antibody-drug conjugate for the treatment of solid tumors [abstract]. Proceedings of the American Association for Cancer Research Annual Meeting 2019; Atlanta, GA. Cancer Res 2019;79(13 Suppl):Abstract nr 2688.