Anti-Human CD276 (B7-H3) (Mirzotamab) (IVMB0521)

CD276, also known as B7 homolog 3 protein (B7-H3), is a member of the B7 superfamily and acts as an immune checkpoint molecule and a costimulatory/coinhibitory immunoregulatory protein¹. CD276 influences innate and adaptive immunity, regulates the aggressiveness of cancer cells, and is thought to play an important role in tumor development and cancer immunity. CD276 has been studied in many cancers, including breast, lung, ovarian, brain, gastric, and squamous cell carcinoma.

Human CD276 exists as either a soluble isoform or as a ~45–66 kDa type I transmembrane protein that is composed of an extracellular domain, a transmembrane domain, and a short intracellular domain¹. Soluble CD276 is produced by cleavage from the cell surface or via alternative intron splicing and has been found in the secretomes of exosomes and other extracellular vesicles.

In normal human tissues, CD276 mRNA is widely and abundantly expressed but protein abundance is low¹. miR-124 is thought to cause translational repression of CD276 by targeting its 3’-UTR, while other miRNAs are known to affect CD276 expression. In tumor cells, CD276 mRNA and protein are abundant, and its presence is correlated with worsened prognosis, poor survival, recurrence rate, and enhanced invasive and migratory properties^{1, 2}. CD276 is known to act as a T cell inhibitor that promotes tumor proliferation and invasion and is an immune checkpoint molecule in the epithelial mesenchymal transition pathway².

Blocking CD276 with monoclonal antibodies reduces tumor growth and prolongs survival in mouse models of various cancers ^{1, 2}. Additionally, a first-in-human study shows that monotherapy with mirzotamab clezutoclax, a first-in class antibody drug conjugate composed of mirzotamab conjugated via a solubilizing linker to a B cell lymphoma – extra long (BCL-XL) inhibitor, has potential anti-tumor activity^{3, 4}.