1008P - Preliminary clinical PK and PD analysis of a phase I study of ZL-1218, a humanized anti-CCR8 IgG1 antibody, in patients with advanced solid tumors

Background

Regulatory T cells (Tregs) play a key role in inhibiting immune responses in the tumor microenvironment (TME). ZL-1218, an anti-CCR8 IgG1 antibody, targets tumor-associated CCR8+ Tregs and induces antibody-dependent cellular cytotoxicity (ADCC)-mediated depletion. Here we present preliminary PK and PD assessments from an ongoing dose escalation clinical trial (NCT05859464).

Methods

PK analysis of ZL-1218 was assessed using a validated enzyme-linked immunosorbent assay (ELISA) at baseline and post-exposure timepoints. PD assessments in peripheral blood were analyzed for changes relative to baseline of Tregs and other immunophenotyping including T cell subsets and inflammatory cytokines. Paired tumor samples were obtained prior to treatment and on C2D8.

Results

5 patients treated over 2 dose levels were available for analysis. Preliminary PK data showed a more than dose proportional increase of C_max and AUC from 0.3 mg/kg to 1 mg/kg. The concentration-time profile was consistent with prediction based on a population PK model scaled from non-human primate data. ZL-1218 depleted >50% of circulating Foxp3+ Tregs from the peripheral blood within 24 hours of the first dose of 0.3 mg/kg (n=1) and a mean reduction of 70% following the 1.0 mg/kg (n=4) dose. IHC analyses of paired tumor biopsies from 2 patients treated at the 1mg/kg dose level demonstrated reductions of more than 60% in CCR8+ cells and increased of CD8+ T cells.ZL-1218 depleted >50% of circulating Foxp3+ Tregs from the peripheral blood within 24 hours of the first dose of 0.3 mg/kg (n=1) and a mean reduction of 70% following the 1.0 mg/kg (n=4) dose. IHC analyses of paired tumor biopsies from 2 patients treated at the 1mg/kg dose level demonstrated reductions of more than 60% in CCR8+ cells and increased of CD8+ T cells.

Conclusions

ZL-1218 was observed to mediate Foxp3+ Treg depletion in the periphery. In addition, paired tumor biopsies revealed CCR8+ cell depletion and concomitant CD8+ cell increase, suggesting ZL-1218’s potential to modulate the TME. These data will be updated in the final poster presentation.

Clinical trial identification

NCT05859464.

Editorial acknowledgement

Legal entity responsible for the study

Zai Lab.

Funding

Zai Lab.

Disclosure

J. Yi, M. Tea, X. Shen, H.C. Gong, X. Pu: Financial Interests, Personal, Full or part-time Employment: Zai Lab (US) Llc; Financial Interests, Personal, Stocks/Shares: Zai Lab (US) Llc. K. Ma: Financial Interests, Personal, Full or part-time Employment: Zai Lab (Shanghai) Co., Ltd; Financial Interests, Personal, Stocks/Shares: Zai Lab (Shanghai) Co., Ltd. O.Mirallas: Financial Interests, Personal, Invited Speaker: ROVI; Financial Interests, Institutional, Writing Engagement: Roche, Merck. Other, Travel Expenses: Kyowa Kirin, Almirall, Recordati. Other, Travel Expenses and Conference Fee: Sanofi. Y: Guo: Financial Interests, Personal, Invited Speaker: BeiGene, BMS, Merck Serono, MSD, Roche. All other authors have declared no conflicts of interest.