143P - Advancing Cancer Immunotherapy via HLA-G Pathway Modulation with UCB4594

Background

Human leukocyte antigen-G (HLA-G), a tolerogenic protein usually restricted to the placenta, is upregulated by many solid cancers where it promotes tumour immune evasion by engaging inhibitory receptors immunoglobin-like transcript (ILT)2 and ILT4 on lymphoid and myeloid cells.UCB4594, a humanized afucosylated IgG1 HLA-G antibody, was developed to promote therapeutic tumour immune rejection by blocking interaction of HLA-G with ILT2 and ILT4 as well as direct induction of tumour cell death via natural killer (NK) cells, macrophages and complement.

Methods

Functional properties of UCB4594 were evaluated using a suite of in vitro assays including assessment of NK cell killing, complement dependent lysis, and antibody-dependent cellular phagocytosis (ADCP) of tumour targets. To further support its therapeutic potential, UCB4594-induced tumour cell killing dependent on tumour infiltrating immune cells was evaluated in 20 primary solid human tumours (10 renal and 10 colorectal) using an ex-vivo human tumoroid platform.

Results

UCB4594 exhibited strong affinity for HLA-G (4-6 nM for soluble HLA-G; <0.025 nM for cell expressed HLA-G), and high selectivity (no binding to other HLA-I molecules on transfected cells or human CD4 T-cells from 60 donors). UCB4594 effectively disrupted interaction of HLA-G with ILT2 and ILT4. UCB4594 induced NK cell killing of 85% and 40% of HLA-G transfected HCT116 cells and naturally HLA-G expressing JEG3 cells, respectively and activated potent complement-dependent lysis of HLA-G expressing Reh cells. UCB4594's dual mechanisms promoting phagocytosis are driven by Fc receptor-mediated ADCP and HLA-G receptor blocking (depletion of 22.0±10.8% of target cells at 0.1 μg/mL and 44.8±8.6% at 10 μg/mL), activity that was enhanced in the presence of anti-CD47. Across 20 human tumours, UCB4594 IgG1 led to 1.5-fold higher tumour cell death than the isotype control in 9 tumours, seen at 24h/72h post-treatment.

Conclusions

These findings support the development of UCB4594 as a novel cancer immunotherapy for application in several solid tumour indications.

Editorial acknowledgement

Medical writing support for this abstract was provided by Enago Life Sciences, India.

Legal entity responsible for the study

UCB Pharma.

Funding

UCB Pharma.

Disclosure

A.L. White, R. McElhone, G. Le Friec, T. Colley, V. O’Dowd: Financial Interests, Personal, Full or part-time Employment: UCB Pharma. C. Thompson, C. Berteau: Financial Interests, Personal, Full or part-time Employment: UCB Pharma; Financial Interests, Personal, Stocks/Shares: UCB Pharma.