Abstract 2963: CDX-585, a novel bispecific antibody targeting PD-1 and ILT4

Abstract Both PD-1 and ILT4 (LILRB2, CD85d) have well established immunosuppressive effects that enable tumors to evade anti-tumor immunity. Tumor expression of PD-L1 and ILT4 has been associated with poor clinical outcomes in several cancer types. Recently, ILT4 activation has been postulated as a resistance mechanism for PD-1/PD-L1 blockade prompting the investigation of dual blockade of these pathways. Siu, L.L. et al. (2022 Clin Cancer Res 28: 57-70) reported encouraging results of the initial clinical study combining the ILT4 antagonist mAb MK-4830 with pembrolizumab. The combination was generally well tolerated and led to several durable responses including in PD-1/PD-L1 refractory patients. We have combined novel PD-1 (mAb E1A9) and ILT4 (mAb 7B1) antagonist antibodies into a tetravalent IgG-scFv format bispecific antibody (bsAb, CDX-585). CDX-585 was engineered to avoid effector functionality by eliminating interaction with Fcγ receptors, and to increase its half-life by enhancing binding to FcRn. As expected, CDX-585 inhibits interaction of PD-1 and ILT4 with their ligands, results in potent inhibition of PD-1 signaling and enhances myeloid cell inflammatory responses to stimulation through toll like receptors (LPS) or CD40 (CD40 agonist mAb). In mixed lymphocyte reactions CDX-585 promoted greater T cell activation than the combination of the parental mAbs. Similarly, CDX-585 demonstrated superior anti-tumor activity over the combination of the parental mAbs in a humanized mouse model of melanoma. CDX-585 has completed GMP manufacturing and IND-enabling activities. Doses of CDX-585 up to 60 mg/kg were well tolerated in cynomolgus macaques and displayed a favorable pharmacokinetic profile. Together these data demonstrate that CDX-585 effectively combines PD-1 and ILT4 blockade into one molecule with favorable biophysical and functional characteristics supporting the initiation of a dose-escalation clinical trial in patients with advanced solid tumors. Citation Format: Lawrence J. Thomas, Laura A. Vitale, Michael Murphy, Collin Xia, Zeyu Peng, Asma Ejas, Montu Patel, James Boyer, April R. Baronas, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Mark Ma, Mingjiu Chen, Hugh M. Davis, Russ A. Hammond, Cherie Taglienti, Michael Yellin, Joel Goldstein, Diego Alvarado, Henry C. Marsh, Tibor Keler. CDX-585, a novel bispecific antibody targeting PD-1 and ILT4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2963.