High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules

Citation
Gp. Adams et al., High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules, CANCER RES, 61(12), 2001, pp. 4750-4755
Citations number
20
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
61
Issue
12
Year of publication
2001
Pages
4750 - 4755
Database
ISI
SICI code
0008-5472(20010615)61:12<4750:HARTLA>2.0.ZU;2-J
Abstract
Antitumor monoclonal antibodies must bind to tumor antigens with high affin ity to achieve durable tumor retention. This has spurred efforts to generat e high affinity antibodies for use in cancer therapy. However, it has been hypothesized that very high affinity interactions between antibodies and tu mor antigens may impair efficient tumor penetration of the monoclonal antib odies and thus diminish effective in vivo targeting (K, Fujimori et al., J, Nucl, Med., 31: 1191-1198, 1990), Here we show that intrinsic affinity pro perties regulate the quantitative delivery of antitumor single-chain Fv (sc Fv) molecules to solid tumors and the penetration of scFv from the vasculat ure into tumor masses. In biodistribution studies examining a series of rad ioiodinated scFv mutants with affinities ranging from 10(-7)-10(-11) M, qua ntitative tumor retention did not significantly increase with enhancements in affinity beyond 10(-9) M, Similar distribution patterns were observed wh en the scFv were evaluated in the absence of renal clearance in anephric mi ce, indicating that the rapid renal clearance of the scFv was not responsib le for these observations. IHC and IF evaluations of tumor sections after t he i,v, administration of scFv affinity mutants revealed that the lowest af finity molecule exhibited diffuse tumor staining whereas the highest affini ty scFv was primarily retained in the perivascular regions of the tumor, Th ese results indicate that antibody-based molecules with extremely high affi nity have impaired tumor penetration properties that must be considered in the design of antibody-based cancer therapies.