A newly-constructed antibody-like molecule containing the gp120-binding domain of the receptor for human immunodeficiency virus blocks HIV-1 infection of T cells and monocytes. Its long plasma half-life, other antibody-like properties, and potential to block all HIV isolates, make it a good candidate for therapeutic use.

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Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125 Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125 I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 μg (9-10 μCi) in 50 μl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.

The HER2 protooncogene encodes a 185-kDa transmembrane protein (p185HER2) with extensive homology to the epidermal growth factor (EGF) receptor. Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma. These data also support the hypothesis that p185HER2 present on the surface of overexpressing tumor cells may be a good target for receptor-targeted therapeutics. The anti-p185HER2 murine monoclonal antibody (muMAb) 4D5 is one of over 100 monoclonals that was derived following immunization of mice with cells overexpressing p185HER2. The monoclonal antibody is directed at the extracellular (ligand binding) domain of this receptor tyrosine kinase and presumably has its effect as a result of modulating receptor function. In vitro assays have shown that muMAb 4D5 can specifically inhibit the growth of tumor cells only when they overexpress the HER2 protooncogene. MuMAb 4D5 has also been shown to enhance the TNF-alpha sensitivity of breast tumor cells that overexpress this protooncogene. Relevant to its clinical application, muMAb 4D5 may enhance the sensitivity of p185HER2-overexpressing tumor cells to cisplatin, a chemotherapeutic drug often used in the treatment of ovarian cancer. In vivo assays with a nude mouse model have shown that the monoclonal antibody can localize at the tumor site and can inhibit the growth of human tumor xenografts which overexpress p185HER2. Modulation of p185HER2 activity by muMAb 4D5 can therefore reverse many of the properties associated with tumor progression mediated by this putative growth factor receptor. Together with the demonstrated activity of muMAb 4D5 in nude mouse models, these results support the clinical application of muMAb 4D5 for therapy of human cancers characterized by the overexpression of p185HER2.

Background and ObjectivesTwo phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).MethodsA parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).ResultsCoadministration of gemfibrozil increased the composite area under the plasma concentration–time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.ConclusionsIf a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0283-1) contains supplementary material, which is available to authorized users.

Background and ObjectivesOral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide.MethodsResults are reported from five clinical studies.ResultsIn a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30–360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration–time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child–Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (Ctrough) versus overall survival (n = 1103) showed that active treatment Ctrough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of Ctrough was associated with a statistically significant better response.ConclusionsEnzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0271-5) contains supplementary material, which is available to authorized users.

Molecular fusions of CD4, the receptor for human immunodeficiency virus (HIV), with immunoglobulin (termed CD4 immunoadhesins) possess both the gp120-binding and HIV-blocking properties of recombinant soluble CD4, and certain properties of IgG, notably long plasma half-life and Fc receptor binding. Here we show that a CD4 immunoadhesin can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells, although, unlike natural anti-gp120 antibodies, it does not allow ADCC towards uninfected CD4-expressing cells that have bound soluble gp120 to the CD4 on their surface. In addition, CD4 immunoadhesin, like natural IgG molecules, is efficiently transferred across the placenta of a primate. These observations have implications for the therapeutic application of CD4 immunoadhesins, particularly in the area of perinatal transmission of HIV infection.

The pharmacokinetics, tissue distribution, and efficacy of a systemic gene transfer method were examined in male BALB/c mice (6-8 weeks old) using 33P-labeled plasmid DNA for luciferase. The DNA was delivered via tail vein injection in saline ([33P]DNA) or in a cationic lipid formulation ([33P]DNA/lipid). One group of mice received approximately equal to 1-3 microCi (45 micrograms of DNA) of either formulation, and mice were euthanized at 2 and 20 min, and 1 and 24 h postdose (2 mice/time point). Blood and plasma radioactivity were quantified, and whole body autoradiographic (WBAR) images were obtained from 20-microns whole body sections. A tissue distribution (TD) study was conducted in a second group of mice, which received approximately equal to 4-6 microCi (45-60 micrograms of DNA) of [33P]DNA/lipid. Mice were euthanized at 1.5 h (1 mouse; [33P]DNA/lipid) or 24 h (2 mice/ group), and organ radioactivity and luciferase expression were measured in lung, liver, kidney, spleen thymus, and parotid salivary gland by direct quantitation methods. Microautoradiography (MAR) was performed on a third group of mice (n = 2), which received 3 microCi (45 micrograms of DNA) of [33P]DNA/lipid and were euthanized at 24 h postdose. For WBAR, the [33P]DNA/lipid tissue distribution (% dose equiv/g) at 2 min was lung >> liver > spleen (red pulp) > kidney (cortex); at 24 h the ranking was spleen (red pulp) > liver > lung, kidney (cortex). The [33P]DNA organ distribution observed at 2 min was liver >> spleen (red pulp) > lung, blood > kidney (cortex); at 24 h the ranking was liver, spleen (red pulp) > kidney (cortex) > lung, blood. High levels of radioactivity in bone (cortical, marrow, growth plate) in both groups may represent uptake of the 33P-labeled test articles by the cellular component of the bone marrow, particularly macrophages, as well as deposition of [33P]phosphate in the bone matrix following metabolism of the [33P]DNA. In the luciferase component of the study, no expression was observed in the [33P]DNA group at 24 h. The [33P]- DNA/lip group exhibited expression as early as 1.5 h in the lung; at 24 h, expression was seen in all the organs examined. Microautoradiography of 24-h tissue samples revealed radioactivity in hepatic Kupffer cells, reticuloendothelial system cells in the marginal zone of the spleen, and diffusely along alveolar septae with scattered accumulations in alveolar macrophages. The results of the WBAR, TD, MAR, and luciferase assay show that the use of cationic lipids significantly altered the biodistribution and resulting expression of the DNA plasmid. Further, 33P (0.25 MeV beta, half-life = 25 days) was shown to be an excellent radionuclide for quantitative WBA and MAR, providing sharp images with less personal hazard and greater ease of handling than 32P (1.71 MeV beta, half-life = 14.3 days).