ACTIONS OF AN IGF-I-ENHANCING ANTIBODY ON IGF-I PHARMACOKINETICS AND TISSUE DISTRIBUTION - INCREASED IGF-I BIOAVAILABILITY

We have previously demonstrated that a specific anti-IGF-I antibody wi ll enhance the growth-promoting activity of IGF-I in vivo (Stewart ef al. 1993). Since the antibody had a modest affinity for IGF-I we sugge sted that the antiserum might protect IGF-I from degradation whilst ma intaining it in a bioavailable form. The aim of this investigation was to test that hypothesis by determining the plasma clearance and tissu e distribution of tracer IGF-I in the presence of the enhancing anti-I GF-I immunoglobulin (anti-IGF-I Ig) or non-immune immunoglobulin (NI I g). Dwarf rats were treated with saline, NI Ig or anti-IGF-I Ig for 4 days. On day 4, I-125-IGF-I (1.6 x 10(7) c.p.m.) was injected into the jugular vein and blood sampled over the next 330 min when the rats we re killed; samples of liver, kidney and skeletal muscle were quickly d issected out. Mean plasma trichloroacetic acid (TCA)-precipitable I-12 5-IGF-I was always significantly greater (P<0.001 for each time point) from anti-IGF-I Ig rats versus the NI Ig or saline groups (which exhi bited practically identical decay curves), implying increased binding capacity for IGF-I in the anti-IGF-I Ig rats. Pharmacokinetic paramete rs were calculated by resolution of the decay curves using a two-phase model. The total clearance rate of I-125-IGF-I was significantly decr eased (P<0.001) by almost twofold in the anti-IGF-I versus the two con trol groups, consistent with the increased binding capacity in the ant i-IGF Ig rats. The half-lives of the faster-decaying phase were not si gnificantly different between treatment groups but, surprisingly, that for the slower-decaying phase was significantly decreased (P<0.001) i n the anti-IGF-I Ig rats versus the two control groups; this may refle ct the low affinity of the anti-IGF-I Ig for IGF-I and its enhancing p roperties. The degradation of I-125-IGF-I was significantly decreased in animals receiving the anti-IGF-I Ig. In support of this, kidney TCA -precipitable radioactivity (c.p.m.) was seven fold less (P<0.001) in the anti-IGF-I Ig groups versus the controls, indicative of reduced ex cretion. Liver TCA-precipitable radioactivity was increased (P<0.001) in the anti-IGF-I Ig rats, probably due to reticuloendothelial clearan ce of non-self antibodies; skeletal muscle TCA-precipitable radioactiv ity tended to increase in the anti-IGF-I Ig group versus the controls which might indicate increased targeting of IGF-I to muscle. Size excl usion chromatography of plasma 15 and 120 min after administration of I-125-IGF-I demonstrated a broad peak of radioactivity with a molecula r mass of 150-300 kDa in the anti-IGF-I Ig-treated rats, which was res ponsible for more than 90% of the eluted radioactivity. This suggests that: (1) I-125-IGF-I was bound to the anti-IGF-I Ig and might also be able to associate with IGFBPs or (2) the polyclonal antibody might re cognise more than one antigenic site on IGF-I. These data indicate tha t the anti-IGF-I Ig was protecting IGF-I from degradation, leading to a larger plasma pool of IGF-I but that IGF-I could be transferred read ily from the plasma pool to tissues. We suggest that administration of IGF-I in conjunction with a binding molecule similar to the antibody described here could provide the basis for effective IGF-I treatment s trategy.