A novel anti-FGFR1 monoclonal antibody OM-RCA-01 exhibits potent antitumor activity and enhances the efficacy of immune checkpoint inhibitors in lung cancer models

Article

Author: Khochenkova, Y. ; Olshanskaya, A. ; Makhov, P. ; Makhov, P ; Khochenkova, Yulia ; Tsimafeyeu, I ; Tsimafeyeu, Ilya ; Khochenkov, D. ; Tsimafeyeu, I. ; Ovcharenko, D ; Khochenkov, D ; Ovcharenko, Dmitriy ; Khochenkov, Dmitry ; Ovcharenko, D. ; Smith, J. ; Olshanskaya, Anna ; Smith, Jonathan ; Khochenkova, Y ; Smith, J ; Makhov, Petr ; Olshanskaya, A

BackgroundFibroblast growth factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors.Materials and methodsLung cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and in vivo, mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established.ResultsThe antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm³ and 2174 mm³ in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses.ConclusionsOur preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this interaction.

01 Nov 2019·Poultry ScienceQ2 · AGRICULTURAL & FORESTRY SCIENCE

Effect of anti-fibroblast growth factor receptor 1 antibodies on phosphorus metabolism in laying hens and their progeny chicks

Q2 · AGRICULTURAL & FORESTRY SCIENCE

ArticleOA

Author: Ren, Zhouzheng ; Ramuta, Mitchell ; Yang, Xiaojun ; Cook, Mark E ; Crenshaw, Thomas D ; Zeng, Qiufeng ; Bütz, Daniel E ; Yang, Xin ; Zhang, Keying

Targeting fibroblast growth factor 23 (FGF-23) signaling pathway is of interest in controlling body phosphate metabolism. This study investigated the effect of anti-fibroblast growth factor receptor 1 (FGFR1, major FGF-23 receptor in the kidney) antibodies on phosphate metabolism. White Leghorn laying hens (65-wk-old) were vaccinated with either a FGFR1 peptide vaccine (five 8-amino-acid peptides were selected, CrZ-1:LPEDPRWE, CrZ-2:LDKDKPNR, CrZ-3:RRPPGMEY, CrZ-4:GSPYPGVP, and CrZ-5:RMDKPSNC) or adjuvant control. At peak antibody titer, hens were artificially inseminated. Chicks from control-vaccinated hens were fed either a non-phytate phosphorus (nPP) sufficient (nPP = 0.45%, positive control) or deficient (nPP = 0.20%, negative control) diet, while chicks from each of the FGFR1 peptide vaccinated hens were fed with the above nPP-deficient diet, for 14 D. When compared to control hens, plasma phosphate in CrZ-1, CrZ-2, CrZ-3, CrZ-4, and CrZ-5 vaccinated hens were decreased by 33, 30, 24, 20, and 26%, respectively (P < 0.05); egg weight in CrZ-2 and CrZ-5 vaccinated hens were increased by 6 and 7%, respectively (P < 0.05); egg production in CrZ-3, CrZ-4, and CrZ-5 vaccinated hens tended to decrease (P = 0.085; decreased by 14, 15, and 13%, respectively). When compared to positive control, chicks from all other groups had decreased body weight gain (BWG) and feed intake (FI) during 1 to 14 D, and had decreased plasma phosphate, tibiotarsus ash, and 24-h phosphorus excretion on day 14. When compared to negative control, BWG of CrZ-1, CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 23, 28, 26, and 20%, respectively (P < 0.05); FI of CrZ-1, CrZ-2, and CrZ-3 antibody chicks were decreased by 15, 15, and 18%, respectively (P < 0.05); plasma phosphate of CrZ-5 antibody chicks were decreased by 26% (P < 0.05); plasma FGF-23 levels of CrZ-4 antibody chicks were increased by 18% (P < 0.05); tibiotarsus ash content of CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 20, 20, and 21%, respectively (P < 0.05). In conclusion, anti-FGFR1 peptide antibodies decreased egg production of hens and growth performance of their progeny chicks probably by activating FGF-23 signaling and stimulating FGF-23 production.

01 Nov 2017·Molecular MetabolismQ2 · MEDICINE

FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes

Q2 · MEDICINE

ArticleOA

Author: Kates, Lance ; Kolumam, Ganesh ; Phamluong, Khanhky ; Chen, Mark Z ; Sonoda, Junichiro ; Newman, Robert ; Chang, Joshua C ; Thai, Minh ; Nunez, Victor ; Zavala-Solorio, Jose ; Flanagan, Sean ; Warming, Søren ; Ziai, James ; Bai, Xiaobo ; Ogasawara, Annie

OBJECTIVEFibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor βKlotho. Previously, recombinant antibody proteins that activate the FGFR1/βKlotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied.METHODSWe investigated the mechanism by which anti-FGFR1/βKlotho bispecific antibody (bFKB1) stimulates thermogenesis in UCP1-expressing brown adipocytes using genetically engineered mice. Anti-FGFR1 agonist antibody was also used to achieve brown adipose tissue restricted activation in transgenic mice.RESULTSStudies with global Ucp1-deficient mice and adipose-specific Fgfr1 deficient mice demonstrated that bFKB1 acts on targets distal to adipocytes and indirectly stimulates brown adipose thermogenesis in a UCP1-independent manner. Using a newly developed transgenic system, we also show that brown adipose tissue restricted activation of a transgenic FGFR1 expressed under the control of Ucp1 promoter does not stimulate energy expenditure. Finally, consistent with its action as a FGF21 mimetic, bFBK1 suppresses intake of saccharin-containing food and alcohol containing water in mice.CONCLUSIONSCollectively, we propose that FGFR1/βKlotho targeted therapy indeed mimics the action of FGF21 in vivo and stimulates UCP1-independent brown fat thermogenesis through receptors outside of adipocytes and likely in the nervous system.

100 Deals associated with OM-RCA-001

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Neoplasms	Discovery	RU	Goodwin Biotechnology, Inc.	13 Feb 2012
Kidney Neoplasms	Discovery	FR	PX Therapeutics SA	13 Feb 2012

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