(Cidara) Discovery of a multispecific CD73/PD-1 targeting Drug Fc-Conjugate (DFC), which improves tumor reduction compared to PD-1 monotherapy in a humanized mouse model

Multispecific CD73/PD-1 targeting

April 9, 2024


The approval of PD-(L)1 axis inhibitors have firmly established immunotherapy as an effective cancer treatment option with reduced adverse effects compared with conventional chemotherapy1. However, while anti-PD-(L)1 therapy has demonstrated durable responses, only a small subset of patients respond. One mechanism of tumor escape from anti-PD-1 therapy is via the release of immunosuppressive metabolites such as adenosine. CD73, an extracellular enzyme expressed on immune cells and some tumors, catalyzes the rate limiting step in adenosine production, the conversion of AMP to adenosine2(Figure 1A/B). As a strategy to improve response rates, we developed a first-in class multispecific CD73/PD-1 targeting DFC. Herein, we describe CD73/PD-1-001, a dual targeting DFC comprising a multivalent conjugate of a small molecule CD73 inhibitor stably linked to a proprietary human IgG1 Fc-fusion with a PD-1 inhibitor peptide (Figure 2). This multispecific DFC has the potential for differentiation and increased therapeutic efficacy compared to approved PD-(L)1 inhibitors.

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The hPD-1/hPD-L1 mouse model enables in vivo efficacy assessment and profiling of molecules targeting the human PD-1/PD-L1 axis in fully immunocompetent mice.


The MC38-hPD-L1-LZ clonal cell line expresses high levels of  human PD-L1 and forms solid tumors in vivo. An optimized version of a  luciferase-ZsGreen (LZ) fusion protein is also stably expressed for in vivo imaging and ex vivo tracking.

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