Anti-CD33 antibody (Mab Designs)

We previously demonstrated that the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalized, and decreases those cells’ viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T cell proliferation, and enhances target-cell killing. Gemtuzumab Ozogamicin Therapy in Hemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (GOTHAM) is a phase 2 single-arm clinical trial for which patients were eligible if they had a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing or refractory to treatment at enrollment. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-d intervals: days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Using 2 schedules of GO, we could not convincingly demonstrate safe feasibility in patients with solid cancer, because of neutropenia. However, GO reproducibly and significantly reduced circulating MDSCs. Importantly, there is consistent preliminary evidence that, upon rebound, the monocyte population of CD33+ cells is replaced with nonsuppressive monocytes. These data support the phase 1b dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarizes MDSCs without causing undue neutropenia, paving the way to use GO as an immune potentiator in this patient population.Trial registration: ISRCTN 89158144