A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Nonclinical Characterization of Bexmarilimab, a Clever-1-Targeting Antibody for Supporting Immune Defense Against Cancers
Tekijät: Hollmén Maija, Maksimow Mikael, Rannikko Jenna H, Karvonen Matti K, Vainio Marita, Jalkanen Sirpa, Jalkanen Markku, Mandelin Jami
Kustantaja: AMER ASSOC CANCER RESEARCH
Julkaisuvuosi: 2022
Journal: Molecular Cancer Therapeutics
Tietokannassa oleva lehden nimi: MOLECULAR CANCER THERAPEUTICS
Lehden akronyymi: MOL CANCER THER
Vuosikerta: 21
Numero: 7
Aloitussivu: 1207
Lopetussivu: 1218
Sivujen määrä: 12
ISSN: 1535-7163
eISSN: 1538-8514
DOI: https://doi.org/10.1158/1535-7163.MCT-21-0840
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/176065832
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
