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Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies./
作者:	Khot, Antari .
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	270 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
Contained By:	Dissertations Abstracts International81-10B.
標題:	Pharmaceutical sciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27737500
ISBN:	9781658422192

Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies.
Khot, Antari .

Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 270 p.

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Thesis (Ph.D.)--State University of New York at Buffalo, 2020.

This item must not be sold to any third party vendors.

Antibody-based therapeutics have been in development for treating cancer by increasing specificity and decreasing off-target toxicity. Many therapies, such as antibody-drug conjugates (ADCs), immune cells redirecting bispecific antibodies, and engineered T cells, take advantage of the targeting properties of antibodies to deliver cytotoxic drugs or to harness the power of immune system against cancer. This dissertation focuses on understanding the pharmacokinetics and pharmacodynamics of such therapies. ADCs have small molecule drugs attached to an antibody via chemical or peptide linkers. The idea behind the development of ADCs is that antibodies can be used to target fast internalizing surface receptors in cancer cells and deliver DNA damaging or anti-mitotic agents that lead to cell death. Pharmacokinetics of ADCs is complicated due to the generation of multiple pharmacologically active species in a biological system such as antibody with a different number of payloads attached, shed payload, and naked antibody. All of these species can have different pharmacokinetic behavior due to their size and physicochemical properties. Hence, in chapter 1, we have developed a physiologically-based pharmacokinetic model that describes the PK of all ADC analytes. This model was developed using trastuzumab-DM1 ADC PK in rats. The advantage of PBPK models is that they incorporate species-specific physiology with tumor and drug-related parameters to aid in improving the design of the molecule in the early development stage and can also be translated to predict clinical PK. The model integrated two PBPK models for antibody and small molecule drugs with a mechanistic tumor model to describe the PK of T-DM1 in rats and was able to predict the PK in humans. In chapter 2, we extended the application of the ADC PBPK model to describe the PK of auristatin based ADCs. PK of ADCs conjugated with MMAF was generated using different bioanalytical assays such as radioisotope labeling, LCMS, and ELISA. The model was able to characterize the PK of these ADCs in mice and was employed to a priori predict clinical PK.There have been tremendous advances in developing bispecific antibodies (BsAb) that retarget effector cells to exert cytolytic action on cancer cells. Clinically approved BsAbs bridge T cells to cancer cells by binding to CD3 receptors and tumor-associated antigens (TAA). These stable connections between cells lead to the formation of an artificial immunological synapse and T cells activation. Activated T cells kill cancer cells by granule-mediated pathway. Disposition and efficacy of these molecules depend primarily on the structure of the antibody, kinetics of their binding partners and number of pro-inflammatory T cells at the site-of-action. To understand the complex interplay between multiple systems and drug-specific parameters, we investigated the in vitro and in vivo PK-PD of BsAbs. In vitro efficacy of a tool BsAb that targeted human CEA and mouse CD3 was assessed using flow cytometry-based experiments in Chapter 3. In addition, all target related kinetics were determined experimentally. All system and drug-related parameters were integrated into a mechanistic in vitro PD model to get a holistic overview of the BsAb activity and determine the efficacious concentration. The design of these antibody-based therapeutics can significantly affect its exposure and efficacy, especially the Fc domain of the antibody, which binds to FcRn and Fc gamma receptors. In chapter 4, we explored the in vivo PK-PD of our tool BsAb antibody and compared it with the PK-PD behavior of a BsAb, which did not bind to Fc receptors. A syngeneic mouse with MC38 tumor model expressing human CEA was employed to investigate the PK-PD of these molecules. As expected, fast clearance of the FcRn non-binding antibody was observed. However, we also observed an atypical increase in elimination 7 days post-dosing at the highest dose of FcRn binding BsAb. This is hypothesized to be a manifestation of immunogenic responses such as anti-drug antibody complex formation. A PBPK model that incorporated CD3 and CEA related kinetics was developed to describe the observed PK. Lastly, engineered T cells utilize the power of antibody fragments by targeting TAA on cancer cells. Once the T cells identify the target expressing cells, they exert cytolytic action leading to apoptosis of cancer cells. Even though the T cell therapies have antibody fragments on their surface to guide them to the target cells, T cells themselves have unique disposition behavior. This necessitates the investigation of PK of natural T cells before exploring engineered T cells. To this end, we explored the disposition of exogenously administered T cells in a mouse melanoma model in chapter 5. A radioisotope labeling technique using Cr-51 was used to quantify the disposition in T cells in various tissues of the mouse. Spleen and liver were the tissues with the highest accumulation of T cells, while tumor concentrations were under 1%ID/g. The PK of T cells was characterized by developing a PBPK model that incorporated trafficking and transmigration of T cells into the tissues. In chapter 6, we further explored the effects of immuno-modulatory therapies such as immune checkpoint inhibitors and high doses of IL2. In addition to investigating the PK of natural T cells, we explored the PK of T cell receptor-T cells (TCR-T cells) that target pmel antigen on melanoma cells and ovalbumin on lymphoma cells. TCR-T cells are not genetically engineered cells; however, they are extracted from mice that were immunized with an antigen of interest. This leads to the production of T cells specific for the antigen used for immunization and extracted cells can then be administered to other animals. In summary, the work presented in this dissertation investigates the PK-PD behavior of ADCs, T cell retargeting bispecific antibodies and T cells. The unique features of these molecules were incorporated in a PBPK framework to describe the PK. In addition, the multi-cell PD model for BsAbs was developed to account for the interplay between various molecular species. In the future, such mechanistic models can guide in designing better molecules and predict clinical PK.

ISBN: 9781658422192Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Antibody

Investigating the Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates, T Cells and Bispecific Antibodies.
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506 $a This item must not be sold to any third party vendors.
506 $a This item must not be sold to any third party vendors.
520 $a Antibody-based therapeutics have been in development for treating cancer by increasing specificity and decreasing off-target toxicity. Many therapies, such as antibody-drug conjugates (ADCs), immune cells redirecting bispecific antibodies, and engineered T cells, take advantage of the targeting properties of antibodies to deliver cytotoxic drugs or to harness the power of immune system against cancer. This dissertation focuses on understanding the pharmacokinetics and pharmacodynamics of such therapies. ADCs have small molecule drugs attached to an antibody via chemical or peptide linkers. The idea behind the development of ADCs is that antibodies can be used to target fast internalizing surface receptors in cancer cells and deliver DNA damaging or anti-mitotic agents that lead to cell death. Pharmacokinetics of ADCs is complicated due to the generation of multiple pharmacologically active species in a biological system such as antibody with a different number of payloads attached, shed payload, and naked antibody. All of these species can have different pharmacokinetic behavior due to their size and physicochemical properties. Hence, in chapter 1, we have developed a physiologically-based pharmacokinetic model that describes the PK of all ADC analytes. This model was developed using trastuzumab-DM1 ADC PK in rats. The advantage of PBPK models is that they incorporate species-specific physiology with tumor and drug-related parameters to aid in improving the design of the molecule in the early development stage and can also be translated to predict clinical PK. The model integrated two PBPK models for antibody and small molecule drugs with a mechanistic tumor model to describe the PK of T-DM1 in rats and was able to predict the PK in humans. In chapter 2, we extended the application of the ADC PBPK model to describe the PK of auristatin based ADCs. PK of ADCs conjugated with MMAF was generated using different bioanalytical assays such as radioisotope labeling, LCMS, and ELISA. The model was able to characterize the PK of these ADCs in mice and was employed to a priori predict clinical PK.There have been tremendous advances in developing bispecific antibodies (BsAb) that retarget effector cells to exert cytolytic action on cancer cells. Clinically approved BsAbs bridge T cells to cancer cells by binding to CD3 receptors and tumor-associated antigens (TAA). These stable connections between cells lead to the formation of an artificial immunological synapse and T cells activation. Activated T cells kill cancer cells by granule-mediated pathway. Disposition and efficacy of these molecules depend primarily on the structure of the antibody, kinetics of their binding partners and number of pro-inflammatory T cells at the site-of-action. To understand the complex interplay between multiple systems and drug-specific parameters, we investigated the in vitro and in vivo PK-PD of BsAbs. In vitro efficacy of a tool BsAb that targeted human CEA and mouse CD3 was assessed using flow cytometry-based experiments in Chapter 3. In addition, all target related kinetics were determined experimentally. All system and drug-related parameters were integrated into a mechanistic in vitro PD model to get a holistic overview of the BsAb activity and determine the efficacious concentration. The design of these antibody-based therapeutics can significantly affect its exposure and efficacy, especially the Fc domain of the antibody, which binds to FcRn and Fc gamma receptors. In chapter 4, we explored the in vivo PK-PD of our tool BsAb antibody and compared it with the PK-PD behavior of a BsAb, which did not bind to Fc receptors. A syngeneic mouse with MC38 tumor model expressing human CEA was employed to investigate the PK-PD of these molecules. As expected, fast clearance of the FcRn non-binding antibody was observed. However, we also observed an atypical increase in elimination 7 days post-dosing at the highest dose of FcRn binding BsAb. This is hypothesized to be a manifestation of immunogenic responses such as anti-drug antibody complex formation. A PBPK model that incorporated CD3 and CEA related kinetics was developed to describe the observed PK. Lastly, engineered T cells utilize the power of antibody fragments by targeting TAA on cancer cells. Once the T cells identify the target expressing cells, they exert cytolytic action leading to apoptosis of cancer cells. Even though the T cell therapies have antibody fragments on their surface to guide them to the target cells, T cells themselves have unique disposition behavior. This necessitates the investigation of PK of natural T cells before exploring engineered T cells. To this end, we explored the disposition of exogenously administered T cells in a mouse melanoma model in chapter 5. A radioisotope labeling technique using Cr-51 was used to quantify the disposition in T cells in various tissues of the mouse. Spleen and liver were the tissues with the highest accumulation of T cells, while tumor concentrations were under 1%ID/g. The PK of T cells was characterized by developing a PBPK model that incorporated trafficking and transmigration of T cells into the tissues. In chapter 6, we further explored the effects of immuno-modulatory therapies such as immune checkpoint inhibitors and high doses of IL2. In addition to investigating the PK of natural T cells, we explored the PK of T cell receptor-T cells (TCR-T cells) that target pmel antigen on melanoma cells and ovalbumin on lymphoma cells. TCR-T cells are not genetically engineered cells; however, they are extracted from mice that were immunized with an antigen of interest. This leads to the production of T cells specific for the antigen used for immunization and extracted cells can then be administered to other animals. In summary, the work presented in this dissertation investigates the PK-PD behavior of ADCs, T cell retargeting bispecific antibodies and T cells. The unique features of these molecules were incorporated in a PBPK framework to describe the PK. In addition, the multi-cell PD model for BsAbs was developed to account for the interplay between various molecular species. In the future, such mechanistic models can guide in designing better molecules and predict clinical PK.
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653 $a Pharmacokinetics
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