Anti-HER2/Topoisomerase I Inhibitor/ATR Inhibitor Antibody-drug Conjugate CLIO-8221

**Semantic type:** Pharmacologic Substance

**Definition:** An Fc-engineered antibody-drug conjugate (ADC) composed of a monoclonal antibody directed against the tumor-associated antigen (TAA) human epidermal growth factor receptor 2 (EGFR2; HER2; ErbB2), conjugated, via a stable hydrophilic linker, to a dual payload consisting of a topoisomerase I inhibitor (Topo1i) and an ataxia telangiectasia and Rad3 related (ATR) kinase inhibitor, with potential antineoplastic activity. Upon administration of the anti-HER2/topo1i/ATRi ADC CLIO-8221, the anti-HER2 monoclonal antibody moiety targets and binds to HER2 expressed on tumor cells. Upon cellular uptake and internalization by tumor cell lysosomes, the Topo1i inhibits DNA topoisomerase I activity, thereby inhibiting DNA replication which results in cell cycle arrest and tumor cell apoptosis. The ATRi selectively targets, binds to, and inhibits ATR, thereby inhibiting ATR-mediated signaling. This blocks the downstream phosphorylation of the serine/threonine protein kinase checkpoint kinase 1 (CHK1). This results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, the accumulation of DNA damage, and the induction of tumor cell apoptosis. This allows for synergistic killing of HER2-expressing tumor cells. CLIO-8221 also has a strong bystander effect thereby further killing tumor cells. HER2, a tyrosine kinase receptor, is overexpressed by many cancer cell types. ATR, a serine/threonine protein kinase upregulated in a variety of cancer cell types, plays a key role in DNA repair, cell cycle progression and survival. It is activated by DNA damage caused during DNA replication-associated stress. The addition of ATRi as a payload may overcome Topo1i resistance as ATRi inhibits the DNA damage response (DDR) pathway. Topo1i causes DNA replication-associated stress, activates the DDR pathway, drives DNA repair and prevents apoptosis, which causes Topo1i resistance in tumor cells.

**Synonyms:** - ADC CLIO-8221 - ADC HMBD-802 - Anti-HER2 ADC HMBD-802 - Anti-HER2 Antibody-drug Conjugate CLIO-8221 - Anti-HER2 Dual-payload ADC CLIO-8221 - Anti-HER2/Topo1i/ATRi ADC CLIO-8221 - CLIO 8221 - CLIO-8221 - CLIO8221 - Dual-payload Antibody-drug Conjugate CLIO-8221 - HMBD 802 - HMBD-802 - HMBD802