Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor.

We have characterized platelet-derived growth factor (PDGF) C, a novel growth factor belonging to the PDGF family. PDGF-C is a multidomain protein with the N-terminal region homologous to the extracellular CUB domain of neuropilin-1, and the C-terminal region consists of a growth factor domain (GFD) with homology to vascular endothelial growth factor (25%) and PDGF A-chain (23%). A serum-sensitive cleavage site between the two domains allows release of the GFD from the CUB domain. Competition binding and immunoprecipitation studies on cells bearing both PDGF alpha and beta receptors reveal a high affinity binding of recombinant GFD (PDGF-CC) to PDGF receptor-alpha homodimers and PDGF receptor-alpha/beta heterodimers. PDGF-CC exhibits greater mitogenic potency than PDGF-AA and comparable or greater mitogenic activity than PDGF-AB and PDGF-BB on several mesenchymal cell types. Analysis of PDGF-CC in vivo in a diabetic mouse model of delayed wound healing showed that PDGF-CC significantly enhanced repair of a full-thickness skin excision. Together, these studies describe a third member of the PDGF family (PDGF-C) as a potent mitogen for cells of mesenchymal origin in in vitro and in vivo systems with a binding pattern similar to PDGF-AB.

Redistribution of tricyclic antidepressants in rats using a drug-specific monoclonal antibody: dose-response relationship.

A monoclonal antibody was used to study the dose-response relationship for antibody-mediated redistribution of tricyclic antidepressants (TCA) in rats. The antibody (anti-TCA) was an IgG1 with Ka = 3.0 x 10(8) M-1 for desipramine (DMI) and 2.2 x 10(8) M-1 for imipramine (IMI). Anesthetized rats received 1 mg DMI (10% of the toxic dose), followed in 15 min by anti-TCA iv at doses representing anti-TCA/DMI molar ratios of 0.003, 0.013, and 0.07. Anti-TCA produced prompt, dose-related increases in the serum DMI concentration of 33, 164, and 776%. Similar results were obtained in rats treated with IMI. The highest dose of anti-TCA reduced the concentration of IMI in the heart. In a second protocol, the anti-TCA dose was kept constant and the DMI or IMI dose varied. The increase in serum drug concentration was 1750, 1260, and 150% (DMI) and 1460, 1200, and 170% (IMI) at drug doses of 0.1, 10, and 1000 micrograms. Thus, the percentage increase in serum drug concentration was diminished only 12-fold (DMI) or 9-fold (IMI) by a 10,000-fold increase in drug dose. At the highest anti-TCA/DMI ratio (lowest DMI dose), tissue DMI concentrations were significantly reduced. We conclude that 1) anti-TCA can effect substantial redistribution of a subtoxic dose of DMI or IMI, even when the antibody dose is less than equimolar to the TCA dose, and 2) the extent of TCA redistribution depends upon the doses of both antibody and drug; anti-TCA is most effective when the body burden of TCA is high. These data support the potential therapeutic use of anti-TCA for DMI or IMI toxicity, and should be useful in anticipating the dose and affinity of anti-TCA required.

Pharmacokinetics and toxicity of high doses of antibody Fab fragments in rats.

The treatment of drug toxicity with drug-specific antibody fragments may, for some compounds, require very high doses of antibody fragments. To examine the feasibility of this therapeutic approach, the pharmacokinetics and toxicity of high doses of nonspecific human IgG Fab fragments were studied in rats. Six animals received 7.5 g/kg iv Fab over 1 hr. Maximum serum Fab concentration was 42.1 +/- 9.9 mg/ml. Calculated pharmacokinetic parameters included steady state volume of distribution 0.43 +/- 0.06 liter/kg, t/2 alpha 2.4 +/- 1.4 hr, t/2 beta 16.3 +/- 2.4 hr, and systemic clearance 27.2 +/- 4.4 ml/hr/kg. Urinary excretion accounted for 31.8 +/- 7.5% of the administered dose. These values are similar to those previously reported for much lower doses (5-15 mg/kg) of digoxin-specific Fab fragments in dogs, baboons, and humans. All animals tolerated Fab infusion without changes in blood pressure, heart rate, or electrocardiogram. The serum creatinine concentration and urinary protein excretion were unchanged 1 week after Fab administration. One animal developed a self-limited respiratory illness 1 week after Fab administration, probably because of intercurrent infection. Organ histology 2 weeks after Fab administration was normal in all animals. These data suggest that rapid iv administration of high doses of antibody Fab fragments is feasible and support the potential use of high doses of Fab fragments as a therapy for drug toxicity. Although the possibility of dose-dependent kinetics was not studied, the similarity of the pharmacokinetics of this high Fab dose in the rat to that of lower doses in other species further suggests that the rat may be a suitable species for studying Fab-drug interactions.