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
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.