Nonclinical Characterization of Bexmarilimab, a Clever-1-Targeting Antibody for Supporting Immune Defense Against Cancers




Hollmén Maija, Maksimow Mikael, Rannikko Jenna H, Karvonen Matti K, Vainio Marita, Jalkanen Sirpa, Jalkanen Markku, Mandelin Jami

PublisherAMER ASSOC CANCER RESEARCH

2022

Molecular Cancer Therapeutics

MOLECULAR CANCER THERAPEUTICS

MOL CANCER THER

21

7

1207

1218

12

1535-7163

1538-8514

DOIhttps://doi.org/10.1158/1535-7163.MCT-21-0840(external)

https://research.utu.fi/converis/portal/detail/Publication/176065832(external)



Common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) is a multifunctional type-1 transmembrane protein that plays an important role in immunosuppression against tumors. Clever-1 is highly expressed in a subset of human tumor-associated macrophages and associated with poor survival. In mice, Clever-1 supports tumor growth and metastasis formation, and its deficiency or blockage induces T-cell-dependent killing of cancer cells. There-fore, targeting Clever-1 could lead to T-cell activation and restoration of immune response also in patients with cancer. This is studied in an on-going clinical trial [Macrophage Antibody To INhibit immune Suppression (MATINS); NCT03733990] in patients with advanced solid tumors where bexmarilimab, a humanized IgG4 antibody against human Clever-1, shows promising safety and efficacy. Here, we report the humanization and nonclinical characterization of physicochemical properties, biological potency, and safety profile of bexmarilimab. Bexmarilimab showed high affinity to Clever-1 on KG-1 cells and bound to Clever-1 on the surface of classical and intermediate monocytes derived from healthy human blood. Bexmarilimab inhibited the internalization of its natural ligand acetylated low -density lipoprotein into KG-1 cells and increased TNF alpha secretion from macrophages but did not impair phagocytic clearance. Bex-marilimab did not induce significant cytokine release in human whole-blood cultures, did not contain nonsafe immunogenic gly-cans, or show any significant binding to human Fcy receptors or complement pathway component C1q. In vivo , bexmarilimab showed dose-dependent duration of monocyte Clever-1 receptor occupancy in cynomolgus monkeys but did not induce a cytokine storm up to a dose of 100 mg/kg. In conclusion, these data support the clinical development of bexmarilimab for the restoration of immune response in cancers.

Last updated on 2024-26-11 at 22:21