Monoclonal antibodies for reproductive health: Part I. Preventing sexual transmission of disease and pregnancy with topically applied antibodies.
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Administration, Topical↗
Biomedical subjects
K J Whaley
Publications and source records attributed to K J Whaley.
Nonoxynol-9 protects mice against vaginal transmission of genital herpes infections.
A vaginal application of a commercially available contraceptive jelly containing nonoxynol-9 (N9) prevented vaginal transmission of herpes simplex virus type 2 (HSV-2) infections in the mouse. When N9 jelly was delivered to the vagina with the virus inoculum, 20 s before inoculum, or 5 min before inoculum, mice were completely protected from visible infection (P < .001). Protection lasted for at least 30 min (P < .03), and significant protection occurred even when the N9 jelly was delivered 15 min after the HSV-2 inoculum (P < .05). These results are consistent with results of studies using N9 products in other animal models and suggest that N9-based contraceptive products can provide significant protection against vaginal transmission of enveloped virus infections in animals.
Animals↗
The cat/feline immunodeficiency virus model for transmucosal transmission of AIDS: nonoxynol-9 contraceptive jelly blocks transmission by an infected cell inoculum.
OBJECTIVES: To develop an animal model to study transmucosal lentivirus transmission, and to determine whether topical application of contraceptive jelly can block transmission by an infected cell incoulum. DESIGN: Feline immunodeficiency virus (FIV), a lentivirus similar to HIV, causes an AIDS-like disease in domestic cats. HIV is transmitted primarily across mucosal surfaces, and infected cells may be important in this transmission. We tested the ability of FIV-infected cells to transmit infection across the vaginal, rectal and oral mucosa of the cat, and whether a vaginal contraceptive jelly could prevent such transmission. METHODS: An inoculum consisting of 2 million FIV-infected primary cat T cells was administered vaginally, rectally or orally to female cats that had received either no pretreatment or pretreatment with a contraceptive jelly containing the detergent nonoxynol-9 as spermicide. Transmission was detected by monitoring recipient animals for viral antibodies and by viral cultures of blood leukocytes. RESULTS: A single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina or rectum (10 out of 11 animals became infected). Pretreatment of the vagina (five animals) or rectum (four animals) with contraceptive jelly protected all animals from transmission by the highly infectious inoculum. CONCLUSIONS: The cat/FIV model provides an efficient means to study transmucosal transmission of lentivirus infections, and for assessing vaginal barrier methods that could block transmission. One such method, nonoxynol-9 contraceptive jelly, effectively prevents transmucosal transmission by an FIV-infected cell inoculum.
Animals↗
Controlled vaginal delivery of antibodies in the mouse.
Controlled delivery of monoclonal antibodies to the mucus secretions of the vagina might provide women with passive immunoprotection against both sexually transmitted diseases and unwanted pregnancy. We have developed intravaginal devices composed of poly(ethylene-co-vinyl acetate) (EVAc) that continuously release IgG antibodies for over 30 days into buffered saline, and we have tested these devices in the vagina of mice. Polymeric devices containing either BSA (as a test reagent for proteins) or anti-hCG antibody, when inserted into the vaginas of mice, provided a continuous supply of either BSA or hCG-binding antibodies to the vaginal mucus for 30 days. Antibodies released by the devices achieved high concentration in the mucus within the lumen of the vagina, but did not significantly ascend into the uterine horns, as determined by epifluorescence microscopy of fluorescently labeled mouse IgG and by immunohistochemical localization of rabbit IgG. Our results suggest that long-term intravaginal delivery of functionally intact antibodies can be achieved with devices composed of EVAc.
Administration, Intravaginal↗
Macromolecules released from polymers: diffusion into unstirred fluids.
Polymers that release macromolecules may be useful for preventing and treating human disease. In certain applications of polymeric controlled release, like drug therapy of brain disease and immunoprotection of mucus epithelia, effectiveness may be limited by diffusion through an unstirred fluid near the polymer. Using computer-assisted epifluorescence microscopy, we have examined the local distribution of fluorescently labelled macromolecules released from an ethylene-vinyl acetate copolymer matrix into unstirred layers of phosphate-buffered water and mid-cycle human cervical mucus. Diffusion coefficients in the fluid were determined by observing the concentration profiles as a function of time. Diffusion coefficients determined for fluorescein, bovine serum albumin, and three classes of human immunoglobulins (IgG, sIgA and IgM) in phosphate-buffered water were in good agreement with literature values. For fluorescein, albumin and IgG, diffusion in mucus was comparable with diffusion in water: the largest molecule tested was slowed by only a factor of 3.
Biocompatible Materials↗
Monkey lactate dehydrogenase-C4 as a model for the interaction of enzymes with gossypol.
Lactate dehydrogenase-C4 (LDH-C4) plays a central role in the metabolism of spermatogenic and mature sperm cells as well as being an enzyme which is inhibited by gossypol, a male contraceptive. Racemic and (+)-gossypol have equivalent potency as inhibitors of LDH-C4 purified from ejaculated sperm of cynomolgus monkeys. Analogues of gossypol (gossypol-glycine ester Schiff's base, 6,6-dimethoxygossypol and ethyl gossypol) have quantitatively similar inhibitory effects of LDH-C4 activity; apogossypol hexaacetate, however, has no inhibitory effect. Other effective inhibitors of LDH-C4 are antimycin, naphthoquinones and lithocholic acid. LDH-C4 may serve as a model for understanding gossypol binding domains and contraceptive action.
Animals↗
Optically active gossypol as a circular dichroism probe of interactions with serum albumins.
The (+)-enantiomer of the polyphenolic binaphthyl gossypol, has been shown to be a useful CD probe of interactions with human and bovine serum albumin. (+)-Gossypol binds to albumin with the same affinity as racemic (+/-)-gossypol, as shown by fluorescence quenching, and also displaces bilirubin from its albumin binding site. The CD characteristics of bound gossypol are different in the case of the two proteins.
Animals↗
A circular dichroism study of (+) gossypol binding to proteins.
The circular dichroism bands of (+) gossypol in the spectral region 300-400 nm have been shown to be sensitive to interactions with proteins. Using CD spectroscopy, gossypol has been shown to interact with lactate dehydrogenase, malate dehydrogenase, alkaline phosphatase, lysozyme, protamine and poly-L-lysine. Binding to proteins generally results in a pronounced red shift of the long wavelength CD band (approximately 380-430 nm) accompanied by a reduction in ellipticity. The changes in spectral parameters of the 1Lb binaphthyl transition may reflect a distortion from a nearly perpendicular gossypol conformation, on binding to proteins.
Chemical Phenomena↗
Kinetic characterization of the inhibition of purified cynomolgus monkey lactate dehydrogenase isozymes by gossypol.
This report describes the results of the first step in a sequence of experiments designed to test the hypothesis that the sperm-specific isozyme of lactate dehydrogenase (LDH-C4), is a site of action of the potential male contraceptive agent gossypol. Cynomolgus monkey LDH-A4, LDH-B4 and LDH-C4 were purified and kinetically characterized. LDH-A4 and LDH-B4 exhibited "linear mixed-type" inhibition by gossypol with both lactate and pyruvate as variable substrates. LDH-C4 also exhibited "linear mixed-type" inhibition with lactate as substrate. However, the C4 isozyme exhibited "parabolic mixed-type" inhibition by gossypol and substrate inhibition with pyruvate as substrate, the latter due to abortive complex formation. Of the three isozymes, LDH-C4 exhibited the lowest apparent Km for pyruvate and the highest apparent Km for lactate. The LDH-C4 form was found to be the most sensitive isozyme to gossypol inhibition, since it had the lowest apparent Ki values for gossypol inhibition. The effect of gossypol on coenzyme binding to LDH-C4 was examined and gossypol binding was found to inhibit binding and release of NADH but not NAD+, an effect possibly due to its interaction with the more hydrophobic loop region of LDH-C4.
Animals↗
Using monoclonal antibodies to prevent mucosal transmission of epidemic infectious diseases.
Passive immunization with antibodies has been shown to prevent a wide variety of diseases. Recent advances in monoclonal antibody technology are enabling the development of new methods for passive immunization of mucosal surfaces. Human monoclonal antibodies, produced rapidly, inexpensively, and in large quantities, may help prevent respiratory, diarrheal, and sexually transmitted diseases on a public health scale.
Animals↗