Programmed cell death protein 1 and Cytotoxic T-lymphocyte-associated protein 4 (PD-1/CTLA-4)

Programmed cell death protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are critical inhibitory receptors that function as immune checkpoints to maintain self-tolerance and modulate T-cell responses [1, 2]. PD-1 primarily operates in the peripheral tissues and tumor microenvironment, where it binds to its ligands (PD-L1/PD-L2) to suppress T-cell effector functions [1, 4]. In contrast, CTLA-4 acts during the early priming phase of T-cell activation within lymphoid organs by competing with the costimulatory receptor CD28 for binding to B7 ligands on antigen-presenting cells [2, 4]. Many tumors exploit these pathways to evade immune surveillance, leading to the development of checkpoint inhibitors. Cadonilimab (AK104) is a first-in-class bispecific antibody designed to simultaneously target both PD-1 and CTLA-4, providing a synergistic effect that enhances anti-tumor activity compared to single-agent therapies [3, 4]. This dual-targeting strategy has shown significant clinical benefit in treating advanced malignancies, particularly recurrent or metastatic cervical cancer, by addressing two non-redundant mechanisms of immune suppression [3, 5]. Sources: [1] UniProt Consortium. PDCD1 - Programmed cell death protein 1 (Q15116). [2] UniProt Consortium. CTLA4 - Cytotoxic T-lymphocyte protein 4 (P16410). [3] Akeso, Inc. Cadonilimab (AK104) Product Information and Approval (2022). [4] Keam, S. J. (2022). Cadonilimab: First Approval. Drugs, 82(12), 1333–1339. [5] ClinicalTrials.gov. A Study of AK104 in Patients With Advanced Solid Tumors (NCT03852251).

Other names

PDCD1CTLA4CD279CD152Programmed death 1Cytotoxic T-lymphocyte protein 4PD-1CTLA-4

Dual blockade of the PD-1 and CTLA-4 inhibitory pathways to restore T-cell activation and enhance anti-tumor immune responses.