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Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2–20 mg/kg IMC-001, the AUC0–14d, AUC0—∞, and Cmax generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018).

Background Immunotherapy with immune checkpoint inhibitors such as PD-(L)1 and CTLA-4 blocker has become an important part of cancer treatment. For the cancers resistant to these drugs, however, many other therapeutic targets are being tested to modulate the tumor microenvironment (TME) toward anti-cancer immunity. Due to the functional flexibility, macrophages play an essential role in orchestrating tissue immunity including TME. CD47 is one of the key targets that modulate macrophages, which is often overexpressed on cancer cells.1 When it binds to its receptor, SIRPα, it gives a ‘don’t-eat-me’ signal and inhibits phagocytosis of cancer cells by macrophages.2 IMC-002 is a fully human IgG4 monoclonal antibody targeting human CD47, which has been engineered to possess optimal efficacy and safety profile. IMC-002 does not induce hemagglutination and contains a hinge stabilizing S228P mutation to prevent Fab arm exchange. Methods A series of in vitro functional assays including ligand binding, cell surface binding and phagocytosis assays were performed. Putative epitopes for IMC-002 were identified using synthetic peptide libraries. In vivo efficacy of IMC-002 was tested in human breast cancer models. Pharmacokinetic parameters and toxicity profiles were assessed in mice and cynomolgus monkeys. Results IMC-002 strongly bound to CD47 ligand and to various types of CD47-expressing cancer cells including solid and hematological cancers. IMC-002 also bound to human CD4 T cells and, to a lesser degree, to CD8 T cells, but not to NK or B cells. Interestingly, IMC-002 showed no binding to RBCs which highly express CD47 and thus, did not induce RBC agglutination in vitro. IMC-002 induced phagocytosis of cancer cells by human blood CD14+ monocyte-derived macrophages and strongly suppressed tumor growth in a dose-dependent manner in xenograft animal models. Treating IMC-002 with tumor antigen targeting IgG1 type therapeutics increased phagocytosis compared to single treatment. Epitope mapping analysis revealed that compared to RBC-binding anti-CD47 antibody and a natural ligand, SIRRα-Fc, IMC-002 bound to distinct parts of CD47 antigen, which may be responsible for the cell-selective binding of IMC-002. Consistent with the in vitro data, IMC-002 was well tolerated in cynomolgus monkeys with no adverse effects including hematologic toxicity at doses up to 100 mg/kg. IMC-002 showed a typical pharmacokinetic profile of therapeutic antibody with a half-life of 5–10 days. Given its differential binding profile toward tumor cells vs normal cells such as RBC, preclinical data was thoroughly analyzed to simulate human PK and to come up with the optimal first-in-human dose. Conclusions Preclinical efficacy and safety profiles of IMC-002 provide a strong rationale for assessing therapeutic potential in clinical studies. Particularly, IMC-002 is expected to be beneficial for hematologic cancer patients because it has been engineered to minimize hematological toxicities such as anemia which is a class effect of the CD47-targeting antibodies. The first-in-human (FIH) study of IMC-002 is ongoing in the US sites. The purpose of the study is to assess the safety and tolerability of IMC-002 and determine the recommended Phase 2 dose (RP2D) of IMC-002 in subjects with metastatic or locally advanced solid tumors and relapsed or refractory lymphomas. Ethics Approval All experimental procedures were performed according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the contract research organizations. References Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPα) interaction is a therapeutictarget for human solid tumors. Proc. Natl Acad. Sci. USA 2012;109:6662–6667. Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286–299.