{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/86455"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/86455","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Pharmacokinetic Strategies to Enhance the Efficacy of Anti-Cancer Antibodies in Solid Tumors","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Bordeau, Brandon; 0000-0002-3203-8498"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Balthasar, Joseph","Pharmaceutical Sciences"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-02-21T17:22:36Z","date_published":"2025-02-21T17:22:36Z","updated_at":"2026-07-27T19:05:32Z","subjects":["pharmaceutical sciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/86455","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Balthasar, Joseph","Pharmaceutical Sciences"]},{"key":"dc:creator","label":"Author","values":["Bordeau, Brandon; 0000-0002-3203-8498"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-02-21T17:22:36Z","2020"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["pharmaceutical sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/86455"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","Although the development and regulatory approval of therapeutic monoclonal antibodies (mAb) have shown dramatic growth over the past two decades, the application of mAb for the treatment of solid tumors has yielded only modest benefit. Many physiologic abnormalities are present within solid tumors that limit the uptake and intra-tumoral distribution of mAb, contributing to observations of sub-optimal efficacy. In this dissertation, new strategies are introduced and experimentally evaluated to improve the entry and distribution of antibodies within tumors, and to improve the prediction of tumor exposure following systemic mAb administration. In the first portion of this dissertation, we introduce the use of anti-idiotypic distribution enhancers (AIDEs) that allow transient competitive inhibition of mAb-antigen binding to enable mAb to bypass the binding site barrier (BSB), which limits antibody distribution in solid tumors. Mathematical modeling and simulation were employed to explore desirable characteristics for AIDEs, leading to the prediction that AIDEs with dissociation half-lives between 1-36 hours would provide dramatic enhancements in the within-tumor distribution of mAb. 1HE, a previously reported anti-idiotypic single-domain antibody (sdAb) against trastuzumab, was characterized using in-vitro binding assays and was selected as a lead inhibitor, with a trastuzumab binding half-life of ~17 hours. 1HE co-administration did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1). An image analysis algorithm was developed to evaluate trastuzumab distribution in whole tumor sections following cryosectioning and immunofluorescent staining. 1HE co-administration increased the mean penetration distance of trastuzumab from tumor vasculature by >50% (p<0.001). To evaluate the impact of competitive inhibition on T-DM1 efficacy, 1HE was administered with T-DM1 at a 1.8 mg/kg dose to Nu/J mice bearing NCI-N87 xenografts. 1HE significantly improved T-DM1 efficacy, extending the median survival time, in-comparison to T-DM1 alone, from 29 to 42 days. New 1HE mutants, with trastuzumab binding half-lives between 4-482 hours, were isolated following error-prone PCR and phage display. These mutants may be used to translate the competitive inhibition strategy beyond pre-clinical animal models or extend the strategy to additional trastuzumab-based therapies. The second approach developed in this dissertation explored the application of tumor-targeted matrix modulating enzymes (TTMME) as a means of enhancing mAb distribution in tumors. Clostridial collagenase H (ColH) was used as a model enzyme, and 2Rs15d was used as a model anti-tumor sdAb. Genetic conjugates of ColH with 2Rs15d and the albumin-binding domain 035 (ABD) were expressed recombinantly in the E. coli strain SHuffle. The 2Rs15d-ColH-ABD construct bound HER2 with an equilibrium dissociation constant (KD) of 2.5 nM, bound mouse serum albumin with a KD of 1.5 nM, and retained ColH catalytic activity with ~500 collagenase units/mg of purified protein. Co-administration of 2Rs15d-ColH-ABD with trastuzumab increased trastuzumab uptake into NCI-N87 xenografts, 24 hours after administration, by 2.9-fold. 2Rs15d-ColH-ABD co-administered with T-DM1 significantly decreased the observed tumor growth rate, up to 14 days after administration, in comparison to T-DM1 administered alone, from 0.044 to 0.002 day-1 (p=0.0007). In the final section of this dissertation, a mathematical model-based approach was developed to improve predictions of mAb exposure in tumors, following systemic administration. The strategy, which utilized dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to inform predictions made via physiologically-based pharmacokinetic PBPK modeling, may have utility in increasing the efficacy of mAb therapy by tailoring antibody doses to individual patients. Incorporation of DCE-MRI parameter relationships into a PBPK model substantially improved a priori predictions of cetuximab distribution, for a range of tumor xenograft models. The new approach decreased the mean prediction error of antibody exposure in tumors, in individual mice, from 223 to 69%. The studies outlined in this dissertation have led to the evaluation of three, previously unreported, pharmacokinetic methods to improve the efficacy of anti-cancer antibodies in solid tumors. Our mathematical modeling and preclinical data support the utility of anti-idiotypic distribution enhancers (AIDEs) for improving the penetration and efficacy of mAb therapies. Protein engineering and recombinant expression resulted in the development of a tumor-targeted matrix modulating enzyme (TTMME), 2Rs15d-ColH-ABD, that was shown to increase the tumor distribution and efficacy of anti-tumor antibody-based therapy. Lastly, we showed that tumor-specific DCE-MRI kinetic parameters may be used as covariates to improve the accuracy of PBPK model predictions of mAb exposure in tumors; this modeling paradigm may hold clinical utility in individualizing mAb dosing protocols and stratifying patients for mAb therapy","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Pharmacokinetic Strategies to Enhance the Efficacy of Anti-Cancer Antibodies in Solid Tumors"]}]}],"canonical_facts":{"dc:contributor":["Balthasar, Joseph","Pharmaceutical Sciences"],"dc:creator":["Bordeau, Brandon; 0000-0002-3203-8498"],"dc:date":["2025-02-21T17:22:36Z","2020"],"dc:description":["Ph.D.","Although the development and regulatory approval of therapeutic monoclonal antibodies (mAb) have shown dramatic growth over the past two decades, the application of mAb for the treatment of solid tumors has yielded only modest benefit. Many physiologic abnormalities are present within solid tumors that limit the uptake and intra-tumoral distribution of mAb, contributing to observations of sub-optimal efficacy. In this dissertation, new strategies are introduced and experimentally evaluated to improve the entry and distribution of antibodies within tumors, and to improve the prediction of tumor exposure following systemic mAb administration. In the first portion of this dissertation, we introduce the use of anti-idiotypic distribution enhancers (AIDEs) that allow transient competitive inhibition of mAb-antigen binding to enable mAb to bypass the binding site barrier (BSB), which limits antibody distribution in solid tumors. Mathematical modeling and simulation were employed to explore desirable characteristics for AIDEs, leading to the prediction that AIDEs with dissociation half-lives between 1-36 hours would provide dramatic enhancements in the within-tumor distribution of mAb. 1HE, a previously reported anti-idiotypic single-domain antibody (sdAb) against trastuzumab, was characterized using in-vitro binding assays and was selected as a lead inhibitor, with a trastuzumab binding half-life of ~17 hours. 1HE co-administration did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1). An image analysis algorithm was developed to evaluate trastuzumab distribution in whole tumor sections following cryosectioning and immunofluorescent staining. 1HE co-administration increased the mean penetration distance of trastuzumab from tumor vasculature by >50% (p<0.001). To evaluate the impact of competitive inhibition on T-DM1 efficacy, 1HE was administered with T-DM1 at a 1.8 mg/kg dose to Nu/J mice bearing NCI-N87 xenografts. 1HE significantly improved T-DM1 efficacy, extending the median survival time, in-comparison to T-DM1 alone, from 29 to 42 days. New 1HE mutants, with trastuzumab binding half-lives between 4-482 hours, were isolated following error-prone PCR and phage display. These mutants may be used to translate the competitive inhibition strategy beyond pre-clinical animal models or extend the strategy to additional trastuzumab-based therapies. The second approach developed in this dissertation explored the application of tumor-targeted matrix modulating enzymes (TTMME) as a means of enhancing mAb distribution in tumors. Clostridial collagenase H (ColH) was used as a model enzyme, and 2Rs15d was used as a model anti-tumor sdAb. Genetic conjugates of ColH with 2Rs15d and the albumin-binding domain 035 (ABD) were expressed recombinantly in the E. coli strain SHuffle. The 2Rs15d-ColH-ABD construct bound HER2 with an equilibrium dissociation constant (KD) of 2.5 nM, bound mouse serum albumin with a KD of 1.5 nM, and retained ColH catalytic activity with ~500 collagenase units/mg of purified protein. Co-administration of 2Rs15d-ColH-ABD with trastuzumab increased trastuzumab uptake into NCI-N87 xenografts, 24 hours after administration, by 2.9-fold. 2Rs15d-ColH-ABD co-administered with T-DM1 significantly decreased the observed tumor growth rate, up to 14 days after administration, in comparison to T-DM1 administered alone, from 0.044 to 0.002 day-1 (p=0.0007). In the final section of this dissertation, a mathematical model-based approach was developed to improve predictions of mAb exposure in tumors, following systemic administration. The strategy, which utilized dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to inform predictions made via physiologically-based pharmacokinetic PBPK modeling, may have utility in increasing the efficacy of mAb therapy by tailoring antibody doses to individual patients. Incorporation of DCE-MRI parameter relationships into a PBPK model substantially improved a priori predictions of cetuximab distribution, for a range of tumor xenograft models. The new approach decreased the mean prediction error of antibody exposure in tumors, in individual mice, from 223 to 69%. The studies outlined in this dissertation have led to the evaluation of three, previously unreported, pharmacokinetic methods to improve the efficacy of anti-cancer antibodies in solid tumors. Our mathematical modeling and preclinical data support the utility of anti-idiotypic distribution enhancers (AIDEs) for improving the penetration and efficacy of mAb therapies. Protein engineering and recombinant expression resulted in the development of a tumor-targeted matrix modulating enzyme (TTMME), 2Rs15d-ColH-ABD, that was shown to increase the tumor distribution and efficacy of anti-tumor antibody-based therapy. Lastly, we showed that tumor-specific DCE-MRI kinetic parameters may be used as covariates to improve the accuracy of PBPK model predictions of mAb exposure in tumors; this modeling paradigm may hold clinical utility in individualizing mAb dosing protocols and stratifying patients for mAb therapy","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/86455"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["pharmaceutical sciences"],"dc:title":["Pharmacokinetic Strategies to Enhance the Efficacy of Anti-Cancer Antibodies in Solid Tumors"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:32Z"}