Browsing by keyword "human monoclonal antibody"
Now showing items 1-3 of 3
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Anti-OspA DNA-Encoded Monoclonal Antibody Prevents Transmission of Spirochetes in Tick Challenge Providing Sterilizing Immunity in MiceWe recently developed anti-OspA human immunoglobulin G1 monoclonal antibodies (HuMAbs) that are effective in preventing Borrelia transmission from ticks in a murine model. Here, we investigated a novel approach of DNA-mediated gene transfer of HuMAbs that provide protection against Lyme disease. Plasmid DNA-encoded anti-OspA HuMAbs inoculated in mice achieved a serum antibody concentration of > 6 mug/mL. Among mice injected with DNA-encoded monoclonal antibodies, 75%-77% were protected against an acute challenge by Borrelia-infected ticks. Our results represent the first demonstration of employing DNA transfer as a delivery system for antibodies that block transmission of Borrelia in animal models.
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In Vivo Protection with Human Monoclonal Antibody S315 following Challenge with Diphtheria ToxinBackground: Morbidity and mortality from Corynebacterium diphtheriae is reduced by prompt administration of equine-derived diphtheria anti-toxin (DAT), which is in short supply worldwide. MassBiologics has developed a human monoclonal antibody (S315) to diphtheria toxin to provide a safer alternative to DAT and address critical supply issues. S315 prevents toxin binding to its putative host receptor and S315 pre-mixed with toxin increased survival in a guinea pig model of intoxication. To further evaluate the ability of S315 to provide in vivo protection, we established a post-exposure treatment model. Methods: Female Hartley guinea pigs (300-350g) were challenged subcutaneously with diphtheria toxin (0.03 to 0.09 Lf, limit of flocculation) to identify the minimum lethal dose. To evaluate anti-toxin efficacy, DAT or S315 was administered five hours post-toxin challenge and animals monitored for 30 days for signs of illness (lethargy, dehydration, weak limbs). Serum anti-diphtheria toxin antibodies were measured by ELISA and Vero cell toxin neutralization assays. Results: The minimum lethal toxin dose was 0.09 Lf. To determine the protective dose of DAT, 0.2 IU, 1.0 IU or 5.0 IU was administered intravenously post-toxin challenge (n=4/cohort). All 0.2 IU or 1.0 IU DAT-treated animals died, while one animal treated with 5.0 IU survived. DAT was subsequently evaluated at 5.0 IU, 10 IU, and 20 IU and compared to a cohort receiving 3.5 mg of S315. All untreated animals died within 72 hours and all antibody-treated animals survived. Dehydration was observed more frequently in the 5 IU and 10 IU DAT cohorts compared to the 20 IU and S315 cohorts. Conclusions: Treatment with S315 after diphtheria toxin exposure is protective; further studies will define a minimum effective dose of S315. This model mimics the route and timing of anti-toxin treatment in humans and provides a rigorous preclinical evaluation of a human antibody replacement for equine DAT.
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Pre-exposure Prophylaxis With OspA-Specific Human Monoclonal Antibodies Protects Mice Against Tick Transmission of Lyme Disease SpirochetesBACKGROUND: Tick transmission of Borrelia spirochetes to humans results in significant morbidity from Lyme disease worldwide. Serum concentrations of antibodies against outer surface protein A (OspA) were shown to correlate with protection from infection with Borrelia burgdorferi, the primary cause of Lyme disease in the United States. METHODS: Mice transgenic for human immunoglobulin genes were immunized with OspA from B. burgdorferi to generate human monoclonal antibodies (HuMabs) against OspA. HuMabs were generated and tested in in vitro borreliacidal assays and animal protection assays. RESULTS: Nearly 100 unique OspA-specific HuMabs were generated, and 4 HuMabs (221-7, 857-2, 319-44, and 212-55) were selected as lead candidates on the basis of borreliacidal activity. HuMabs 319-44, 857-2, and 212-55 were borreliacidal against 1 or 2 Borrelia genospecies, whereas 221-7 was borreliacidal (half maximal inhibitory concentration, < 1 nM) against B. burgdorferi, Borrelia afzelii, and Borrelia garinii, the 3 main genospecies endemic in the United States, Europe, and Asia. All 4 HuMabs completely protected mice from infection at 10 mg/kg in a murine model of tick-mediated transmission of B. burgdorferi CONCLUSIONS: Our study indicates that OspA-specific HuMabs can prevent the transmission of Borrelia and that administration of these antibodies could be employed as preexposure prophylaxis for Lyme disease.
