Phase 1 study of ADG126, a novel masked anti-CTLA-4 SAFEbody, that combines tumor-localized activation with strong Treg depletion and soft ligand blocking in patients with advanced solid tumors.
Authors: Richardson Gary Edward , Tolcher Anthony W. , Morris Michelle Frances , de Souza Paul L. , Hamid Anis , She Xiaohong , Zhu Lvyu , Wang Hongyan , Zheng Songmao , Liu Guizhong , Li Yan , Du Fangyong Felix , Fischkoff Steven , Gong Hua , Zha Jiping , Luo Peter 
Published: June 2022

e17601 Background: SAFEbody ADG126, a masked version of NEObody ADG116 (ESMO IO Conference Abstract #394, NCT04501276), targets a unique species-conserved CTLA-4 epitope with preclinical safety and efficacy profiles superior to ipilimumab, an approved anti-CTLA-4 immune checkpoint inhibitor known to cause treatment-related irAEs in ̃70% of patients. ADG126 is designed to unlock the great potential of anti-CTLA-4 immunotherapy in 4 key ways: 1) improving safety through masking to limit on-target off-tumor irAEs in normal tissues, 2) widening the therapeutic window through selective activation in tumor microenvironment (TME), 3) maximizing anti-tumorigenic effects through prolonged exposure and steady accumulation of activated ADG126 in TME, 4) enhancing antitumor potency relative to ipilimumab via a higher Teff/Treg ratio achieved by combining T cell activation and strong ADCC-mediated Treg depletion in TME. We present interim results from our ongoing Phase 1 study of ADG126 (NCT04645069). Methods: ADG126 monotherapy [0.1, 0.3, 1, 3, 10 mg/kg (mpk)] was given to patients with advanced solid tumors Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, ORR per RECIST v1.1, and PFS. Results: For 16 patients treated in dose escalation cohorts (≤10 mpk), the median age was 65 years with 31% receiving >3 prior lines of therapies, and 31% progressed from immuno-oncology (IO) therapy. ADG126 was well-tolerated with no DLTs observed, nor was the MTD reached. Only Grade 1 TRAEs were reported, with fatigue (19%) and pruritis (13%) being most common. Plasma PK was approximately linear with a 1.7-fold increase in the mean t1/2z for the total drug over the intact ADG126, suggesting the activated ADG126 accumulated steadily with > 2 fold accumulation at Ctrough during repeat dosing, resulting in saturating target engagement at 10 mpk. Stable disease was seen in 5/16 patients with 1/5 surpassing > 24 weeks. One ovarian cancer, and 1 uveal melanoma patient who progressed on nivolumab/ipilimumab, showed > 20% durable reductions in target lesions by CT, and increased CD8+ T cells post-dosing. In the same ovarian cancer patient, a 77% reduction in CA-125 occurred after 7 treatment cycles at 1 mpk. Conclusions: ADG126 demonstrated excellent tolerability and safety for continuous dosing beyond 4 cycles at 10 mpk and for more than 8 cycles at 1 mpk. Compared to ADG116, its non-masked parental Ab, ADG126 exhibited superior PK and early efficacy signals correlated with increased peripheral CD8+ T cells, in general. ADG126 may offer better safety and efficacy profile than ipilimumab, which could help realize the full potential of blocking the CTLA-4 pathway. Combination studies of ADG126 with anti-PD-1Ab(s) have been initiated to determine their safety and efficacy in IO-sensitive and resistant cancer types. Clinical trial information: NCT04645069.