{"doi":"10.1093/abt/tbad025","title":"Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML","abstract":"Abstract The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128-3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40–60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128-3/N297A), which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128-3’s effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128-3. When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128-3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15–25% decrease in T-cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128-3 to maintain LILRB4-blocking function. Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.","journal":"Antibody Therapeutics","year":2023,"id":367581,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345196,"name":"Xun Gui","orcid":"0000-0002-5070-3527","position":1,"is_corresponding":false},{"id":345194,"name":"Mi Deng","orcid":"0000-0003-4291-0144","position":2,"is_corresponding":false},{"id":345199,"name":"Ryan Huang","orcid":"0000-0001-8296-5591","position":3,"is_corresponding":false},{"id":625118,"name":"Xiaohua Ye","orcid":"0000-0002-2300-4739","position":4,"is_corresponding":false},{"id":18590,"name":"Peng Zhao","orcid":"0000-0002-9296-5293","position":5,"is_corresponding":false},{"id":726218,"name":"Xuejun Fan","orcid":"0009-0001-4648-0287","position":6,"is_corresponding":false},{"id":244930,"name":"Wei Xiong","orcid":"0000-0002-8087-5047","position":7,"is_corresponding":false},{"id":345206,"name":"Cheng Cheng Zhang","orcid":"0000-0003-4763-3887","position":8,"is_corresponding":false},{"id":284582,"name":"Ningyan Zhang","orcid":"0000-0002-4348-2180","position":9,"is_corresponding":false},{"id":105313,"name":"Zhiqiang An","orcid":"0000-0001-9309-2335","position":10,"is_corresponding":false},{"id":1109364,"name":"Joshua Morse","orcid":"0000-0002-9834-1975","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:15:16.306414Z","pmid":"38235377","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}