Bispecific antibody (ABL602 2 + 1) induced bistable acute myeloid leukemia kinetics

• Published in: Scientific reports 2024-10, Vol.14 (1), p.25557-11, Article 25557
• Main Author: Xu, Shilian
• Format: Article
• Language: English
• Subjects: 631/114; 631/250; 631/67; 631/67/1059/2325; 631/67/1990; 639/705; 639/705/1041; ABL602 2 + 1; Acute myeloid leukemia; Antibodies; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacology; Bispecific antibodies; Bispecific antibody; Bistability; CD3 antigen; CD3 Complex - antagonists & inhibitors; CD3 Complex - immunology; CD8 antigen; Cell activation; Cell culture; Chronic lymphocytic leukemia; Cytotoxicity; HL-60 Cells; Humanities and Social Sciences; Humans; Immunotherapy; Kinetics; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Mathematical models; Models, Theoretical; multidisciplinary; Science; Science (multidisciplinary); T-Lymphocytes - immunology; Tumors; Tumour burden
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-75971-4

ABL602 2 + 1, a bispecific antibody with two distinct domains binding to CLL-1 on leukemias and CD3 on T cells, exhibits superior T cell activation and tumour lysing activity. Treatment outcomes of bispecific antibody rely on acute myeloid leukemia cell replication and antibody induced tumour lysing, but their quantitative relationship was unknown. Mathematical models are employed to quantitatively investigate HL-60 cell kinetics determined by bispecific antibody and tumour burden. First, we analysed cytotoxicity assay data testing HL-60 cell against bispecific antibody and T cells, and found efficiency of bispecific antibody induced tumour lysing increases but saturates with increase of HL-60 cell, T cell and bispecific antibody concentration. As a result, their interaction leads to bistable HL-60 cell kinetics; namely, at a given bispecific antibody and T cell concentration interval, HL-60 cell kinetics with small tumour burdens are inhibited but refractory to large tumour burdens. T cell concentration is strong negatively correlated with HL-60 cell concentration. With bispecific antibody clearance, observed bistable HL-60 cell kinetics still exists. Our finding explains observed phenomenon that bispecific antibody was less efficacious at high tumour burden even with enough activated cytotoxic CD8 + T cells. Maintaining high antibody concentration and preventing T-cell exhaustion are equivalently important to sustain long-term control.