Abstract 4629: Tumor penetration and retention of different sized FGFR4 targeting scaffolds
2012; American Association for Cancer Research; Volume: 72; Issue: 8_Supplement Linguagem: Inglês
10.1158/1538-7445.am2012-4629
ISSN1538-7445
AutoresRuth Muchekehu, Steven Pirie‐Shepherd, Julia Coronella,
Tópico(s)Cancer Genomics and Diagnostics
ResumoAbstract Poor drug concentration, distribution and retention pose significant obstacles to effective therapy of solid tumors. Antibody based immunotherapies must balance pharmacokinetics (PK), molecular weight and potency in order to maximize tumor penetration and retention. Low molecular weight constructs may have superior tumor diffusion properties, but short in vivo half life, whereas whole IgG molecules have improved PK properties and slow heterogeneous penetration. We hypothesise a molecule with a mass of 100-150 kDa and a KD of 1- 10 nM will have the ideal characteristics for maximum tumor penetration. A CovX-Body is the fusion of two targeting moieties (typically a peptide; in this study an FGFR4 targeting peptide is used) with an IgG scaffold. Constructs with variable molecular weights and affinities for FGFR4 have been generated by enzymatic digestion of the CovX body. As measured by ELISA, surface plasmon resonance (SPR), and flow cytometry (FACS), the bivalent CovX-Body and F(ab)2 constructs had similar FGFR4 binding properties (KD = 0.7 nM and 0.8 nM respectively), while the monovalent Fab construct showed ∼10-fold decreased binding (KD =11 nM). Initial in vivo studies measured total tumor levels of the full length CovX-Body in Colo205 Xenografts 72 hours post-injection with various doses. CovX-body levels were measured using an anti-idiotype CovX-body ELISA. The FGFR4-targeting CovX-Body reaches 8-fold higher total tumor levels compared to non-targeting CovX-bodies following a 10 mg/kg dose. Tumor penetration into the centre of the tumor was also measured, and showed 16-fold higher levels of the targeted CovX-body in the centre of the tumor compared to the non-targeting. Future work will involve measuring the biodistribution and tumor penetration properties of the different constructs. Lower molecular weight constructs should rapidly achieve high but transient levels of drug within the tumor, while IgG should achieve longer term, but lower intratumoral concentrations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4629. doi:1538-7445.AM2012-4629
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