期刊
VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY
卷 240, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.vetimm.2021.110322
关键词
Cat; Serum albumin; Antigen-binding fragment (fab); Neutropenia; Granulocyte-colony stimulating factor (G-CSF); Pegfilgrastim
资金
- Aprilbio Co., Ltd.
A long-acting therapeutic feline G-CSF fusion protein was successfully created and showed superior bioactivity and efficacy in cats. This demonstrates the potential of using anti-serum albumin Fab-associated technology for developing valuable long-acting biologics in veterinary medicine.
Off-label use of a human granulocyte colony stimulating factor (hG-CSF) has been allowed to treat dogs and cats with neutropenia. However, repeated administration of hG-CSF induces undesirable anti-drug antibody (ADA) responses, implying the necessity of animal-derived G-CSF as a therapeutic reagent, preferably with a long-acting capability. Herein, we generated a recombinant fusion protein by genetically combining FL335, a chimeric Fab specific for feline serum albumin (FSA), and feline G-CSF (fG-CSF), with the ultimate goal of developing a longacting therapeutic fG-CSF for cats. The resulting FL335-fG-CSF fusion protein, referred to as APB-F1, was produced well as a functional form in a Chinese hamster ovary (CHO) expression system. In in vitro analyses, APB-F1 bound to FSA at high affinity (KD = 400 pM) and possessed 0.78 x 107 U/mg G-CSF biological activity, clearly proving its biological functionality. Pharmacokinetic (PK) and pharmacodynamic (PD) studies using healthy cats revealed that the serum half-life (t1/2) of APB-F1 was increased five times compared with that of fG-CSF (t1/2 = 13.3 h vs. 2.7 h) in subcutaneous (SC) injections. Additionally, APB-F1 induced a profound and sustained increase in white blood cell (WBC) and actual neutrophil count (ANC) up to 10 days, which was far superior to other GCSF preparations, including filgrastim (NeupogenTM) and even pegfilgrastim (NeulastaTM). Conclusively, a longacting fG-CSF with potent in vivo bioactivity was successfully created by using FL335; thus, we provided evidence that our anti-serum albumin Fab-associated (SAFA) technology can be applied reliably in developing valuable long-acting biologics in veterinary medicine.
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