BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression

Abstract

BackgroundCancer immunotherapy has revolutionized cancer treatment. However, considering the limited success of immunotherapy to only some cancer types and patient cohorts, there is an unmet need for developing new treatments that will result in higher response rates in patients with cancer. Immunoglobulin-like transcript 2 (ILT2), a LILRB family member, is an inhibitory receptor expressed on a variety of immune cells including T cells, natural killer (NK) cells and different myeloid cells. In the tumor microenvironment, binding of class I MHC (in particular HLA-G) to ILT2 on immune cells mediates a strong inhibitory effect, which manifests in inhibition of antitumor cytotoxicity of T and NK cells, and prevention of phagocytosis of the tumor cells by macrophages.MethodsWe describe here the development and characteristics of BND-22, a novel, humanized monoclonal antibody that selectively binds to ILT2 and blocks its interaction with classical MHC I and HLA-G. BND-22 was evaluated for its binding and blocking characteristics as well as its ability to increase the antitumor activity of macrophages, T cells and NK cells in various in vitro, ex vivo and in vivo systems.ResultsCollectively, our data suggest that BND-22 enhances activity of both innate and adaptive immune cells, thus generating robust and comprehensive antitumor immunity. In humanized mice models, blocking ILT2 with BND-22 decreased the growth of human tumors, hindered metastatic spread to the lungs, and prolonged survival of the tumor-bearing mice. In addition, BND-22 improved the antitumor immune response of approved therapies such as anti-PD-1 or anti-EGFR antibodies.ConclusionsBND-22 is a first-in-human ILT2 blocking antibody which has demonstrated efficient antitumor activity in various preclinical models as well as a favorable safety profile. Clinical evaluation of BND-22 as a monotherapy or in combination with other therapeutics is under way in patients with cancer.Trial registration numberNCT04717375.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis

“…For instance, MK4830 is an antibody in early phase clinical development targeting the HLA-G receptor, ITL4. In the early phase I study signs of activity were reported in PD-1 pretreated patients ( 51 ) Other studies evaluating antibodies targeting ITL2 such as BND22 are in preclinical and early clinical development ( 12 , 52 ). Early signs of clinical activity have been reported in microsatellite instability-high (MSH-I) colorectal tumors and ovarian cancer, among other tumor types.…”

“…Recently agents targeting HLA-G or their receptors, such as the LILRB family of proteins have shown preclinical activity, and some of these agents have transitioned to clinical testing ( 11 , 12 ). These drugs predominantly act on myeloid derived suppressor cells ( 13 ).…”

Evaluating Mass Spectrometry-Based Hydroxyl Radical Protein Footprinting of a Benchtop Flash Oxidation System against a Synchrotron X-ray Beamline

“…The commercial availability of the semiautomated FOX system could hasten the implementation of HRPF experiments at worldwide mass spectrometry facilities. The use of FOX for protein footprinting has been demonstrated for determining the epitope of TNFα recognized by the adalimumab antibody and measuring the effect of post-translational modifications in a dynamic system like ovalbumin. , Until now, the FOX system applications have been “ in vitro ” protein footprinting experiments in comparison to synchrotron X-rays and FPOP HRPF platforms, which have addressed a wide variety of structural biology questions for diverse macromolecules. ,,,,− The FOX system has the capability to address more challenging questions in future which range from “ in-cell ” protein footprinting to membrane proteins. ,,− We envision that this benchmarking of the FOX protein oxidation system in comparison to synchrotron X-rays under physiological pH and scavenging conditions will spur the adoption of the FOX system’s HRPF applications and advance the HRPF field worldwide.…”

“…HRPF is an umbrella term for covalent labeling approaches employing •OH adducts, where the •OH can be generated by a variety of approaches: radiolysis of water by X-rays, γ-rays, electron beams, electric discharges or plasma sources; decomposition of hydrogen peroxide (H 2 O 2 ) using transition metal-based Fenton chemistry; and photolysis of H 2 O 2 using lasers (FPOP) or a high-pressure flash oxidation lamp. − Among these •OH sources, high-intensity X-ray synchrotron beamlines played an essential role in the beginning of the HRPF field and continue to be important resources for HRPF method development and applications. − X-ray beamlines deliver a measurable, reproducible, and controlled •OH dose on microsecond to millisecond (and longer) time scales. The availability of a high •OH dose at synchrotron beamlines for the structural biology community has allowed studies of complex and highly scavenging systems such as virus assembly, neurodegenerative diseases, epitope mapping, and time-resolved macromolecular dynamics. − Until now, MS analysis steps for X-ray irradiated samples have been carried out at geographically distant sites from the synchrotron, resulting in a slow feedback loop between sample chemistry optimization, beamline experiments, and data analysis . The availability of a benchtop •OH labeling setup for MS facilities in conjunction with MS access at synchrotron X-ray beamlines could and should accelerate the wider adoption of HRPF technology by the structural biology community.…”

Dimerization of Transmembrane Proteins in Cancer Immunotherapy

“…The binding of ILT to HLA-G can inhibit the cytokine secretion, cell differentiation, and cell proliferation of immune cells, and induce cytotoxicity and apoptosis [115]. For example, after ILT4 binds to HLA-G, it can recruit SHP-1/-2 and activate the nuclear factor-κ-gene binding (NF-κB) pathway, leading to the increase in Interleukin-6 (IL-6) level and then the activation of the STAT3 pathway, which affects the function and maturation of DCs and leads to impaired innate immunity [120].…”