Browsing by Subject "Monoclonal Antibody"
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Item Passive Immunization to treat nicotine dependence in rats.(2009-01) Roiko, Samuel A.Cigarette smoking is the leading preventable cause of death in the United States, primarily due to nicotine addiction. Currently available medications are only partially effective in increasing smoking cessation, and additional therapies are needed. Immunotherapy is an alternative strategy for attenuating nicotine's addictive effects. Vaccination against nicotine alters nicotine pharmacokinetics and nicotine's behavioral effects in rats. In clinical trials, nicotine vaccines reduce smoking, but efficacy is limited by high variability and low mean serum nicotine-specific antibody (NicAb) levels. Passive immunization is an alternative method of immunization, and can potentially circumvent the limitations of vaccination by allowing control over the dose and timing of NicAb administration. The overall goal of this thesis was to examine the use of passive immunization to treat tobacco addiction. The specific aims were to characterize the efficacy of passive immunization on nicotine pharmacokinetics and nicotine-induced behavior, explore the effects of combining vaccination with passive immunization, and examine a potential adverse effect of passive immunization, the precipitation of withdrawal. Passive immunization with the nicotine-specific monoclonal antibody Nic311 reduced nicotine clearance and steady-state volume of distribution, and prolonged nicotine's elimination half-life, demonstrating the underlying mechanism of immunotherapy efficacy. Nic311 attenuated nicotine-induced locomotor sensitization, and combining Nic311 with vaccination resulted in greater reductions in brain nicotine levels and nicotine-induced locomotor sensitization compared to either immunotherapy alone, demonstrating the behavioral efficacy of Nic311 and suggesting a possible clinical role as a supplement for vaccination. Administration of Nic311 to nicotine-dependent rats substantially reduced brain nicotine levels but did not elicit a nicotine withdrawal syndrome. These findings demonstrate the benefits and safety of passive immunization with Nic311, and point to its potential in treating nicotine addiction.Item Targeting the Tumor Stroma Using a Monoclonal Antibody Platform Technology(2021-04) Hintz, Hallie1 in 9 men will be diagnosed with prostate cancer during their lifetime and it remains the second leading cause of cancer death among American men. Men who fail standard-of-care androgen deprivation therapy (ADT) and progress to metastatic castration resistant prostate cancer (mCRPC) are left with few therapeutic options. Current second line therapies only provide a small survival benefit and there is a critical unmet need for new and innovative approaches to treat mCRPC. Imaging is a crucial aspect of mCRPC clinical management used for the detection of recurrent or distant disease. The development of new therapies is also dependent on accurate imaging modalities for patient staging and evaluating treatment response. Our research shows fibroblast activation protein alpha (FAP) is a relevant target for imaging and treating mCRPC. FAP is emerging as the next pan-cancer target given its upregulated expression in cancer associated fibroblasts (CAFs) and localization to the tumor microenvironment. Here we document the discovery and validation of a monoclonal antibody that selectively binds to FAP. The lead antibody, B12, was identified from a naïve murine single-chain variable fragment antibody phage display library screened against recombinant human FAP. The heavy and light chains of B12 were cloned into full-length human immunoglobulin 1 vectors and expressed as a chimeric monoclonal antibody (B12 mAb). B12 mAb was shown to detect FAP expression in cell lines and was rapidly internalized by FAP-expressing cells in vitro. B12 mAb demonstrated cross-reactivity with murine FAP, but not with the highly homologous protease human dipeptidyl peptidase IV. PET/CT imaging with [89Zr]Zr-B12 mAb demonstrated high tumor uptake and long-term retention of the probe in several preclinical animal models. Furthermore, we show its superiority to other clinically investigated imaging probes which suggests clinical translation of B12 mAb as a non-invasive mCRPC imaging probe. Next, we evaluated the therapeutic potential of B12 mAb as an antibody-dependent cell-mediated cytotoxicity (ADCC) inducing agent in combination with an engineered NK-92MI CD64 cell therapy. The immunotherapy demonstrated selective cytotoxicity in vitro and treatment effectively controlled tumor growth in an animal model. Furthermore, we engineered B12 mAb as an antibody-drug conjugate (ADC) and showed cytotoxic effect in several in vitro and in vivo solid tumor models. Overall, this research represents a platform technology for the development of theranostics targeting FAP that could provide urgently needed therapies and imaging probes for mCRPC patients.