Nonclinical Characterization of Bexmarilimab, a Clever-1-Targeting Antibody for Supporting Immune Defense Against Cancers
Jalkanen Sirpa; Vainio Marita; Rannikko Jenna H; Karvonen Matti K; Hollmén Maija; Maksimow Mikael; Jalkanen Markku; Mandelin Jami
Nonclinical Characterization of Bexmarilimab, a Clever-1-Targeting Antibody for Supporting Immune Defense Against Cancers
Jalkanen Sirpa
Vainio Marita
Rannikko Jenna H
Karvonen Matti K
Hollmén Maija
Maksimow Mikael
Jalkanen Markku
Mandelin Jami
AMER ASSOC CANCER RESEARCH
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022091258453
https://urn.fi/URN:NBN:fi-fe2022091258453
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]