Abstract 143P
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.
Resources from the same session
60P - Adaptive NK cells as a therapeutic option for childhood leukaemia
Presenter: Zoya Eskandarian
Session: Poster Display
61P - Unlocking the Power of Natural Killer Cells: Precision Selection with Cutting-Edge Microfluidics
Presenter: Neelima KC
Session: Poster Display
63TiP - A phase I study of tumor-infiltrating lymphocytes (TILs) in advanced solid tumors used an optimized regimen: MIZAR trial
Presenter: Qing Xu
Session: Poster Display
68P - Real-world (rw) outcomes in patients (pts) with metastatic (m) NSCLC and STK11, KEAP1 and/or KRAS mutations (mut) receiving PD-(L)1-based treatment (tx): CORRELATE
Presenter: Solange Peters
Session: Poster Display
70P - LIST (Lung Initiative on Sequence Therapy), a real-world study of nivolumab for advanced NSCLC in France: first effectiveness, safety, and IO-rechallenge results
Presenter: Benoît GODBERT
Session: Poster Display
72P - Camrelizumab plus apatinib after chemoradiotherapy in unresectable stage III non-small-cell lung cancer?A multi-center, single-arm, phase 2 study
Presenter: Hui Zhouguang
Session: Poster Display
74P - A single-center, Phase II study of surufatinib combined with toripalimab, pemetrexed(A), and platinum (P) in patients with advanced non-squamous non-small cell lung cancer (nsq-NSCLC)
Presenter: Wen Feng Fang
Session: Poster Display
75P - Patient-reported outcomes (PROs) of cemiplimab + chemotherapy in advanced non-small cell lung cancer (NSCLC): EMPOWER-lung 3 liver metastases subpopulation
Presenter: Ana Baramidze
Session: Poster Display