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  • 1
    Article
    Article
    2012
    ISSN: 0724-8741 
    Language: English
    In: Pharmaceutical research, 2012-06-28, Vol.29 (9), p.2354-2366
    Description: Antibody drug conjugates (ADCs) are a class of therapeutics that combine the target specificity of an antibody with the potency of a chemotherapeutic. This therapeutic strategy can significantly expand the therapeutic index of a chemotherapeutic by minimizing the systemic exposure and associated toxicity of the chemotherapeutic agent, while simultaneously maximizing the delivery of the chemotherapeutic to the target. The abundance of antibody targets, coupled with advances in antibody engineering, conjugation chemistry, and examples of early clinical success, have stimulated interest in developing ADCs. However, developing and optimizing the highly complex components of ADCs remain challenging. Understanding the pharmacokinetics (PK) and consequently the pharmacokinetic-pharmacodynamic (PKPD) properties of ADCs is critical for their successful development. This review discusses the PK properties of ADCs, with a focus on ADC-specific characteristics, including molecular heterogeneity, in vivo processing, and the implications of multiple analytes. The disposition of ADCs and the utility of PKPD modeling are discussed in the context of providing guidance to assist in the successful development of these complex molecules.
    Subject(s): antibody drug conjugates (ADCs) ; Antineoplastic Agents - pharmacokinetics ; Biochemistry ; Biochemistry, general ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering ; Biomedical Engineering and Bioengineering ; Biomedicine ; Expert Review ; general ; General pharmacology ; Humans ; Immunoconjugates - pharmacokinetics ; Medical Law ; Medical sciences ; optimization ; Pharmaceutical technology. Pharmaceutical industry ; pharmacodynamics ; pharmacokinetics ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pharmacy
    ISSN: 0724-8741
    E-ISSN: 1573-904X
    Source: Alma/SFX Local Collection
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  • 2
    Language: English
    In: Journal of clinical oncology, 2010-06-01, Vol.28 (16), p.2698-2704
    Description: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels 〈 10 ng/mL. Clearance at doses 〈 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade 〈 or = 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade 〉 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
    Subject(s): Adult ; Aged ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal, Humanized ; Biological and medical sciences ; Biopsy, Needle ; Bone Neoplasms - secondary ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - mortality ; Breast Neoplasms - pathology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Gynecology. Andrology. Obstetrics ; Half-Life ; Humans ; Immunoconjugates - administration & dosage ; Immunoconjugates - adverse effects ; Immunohistochemistry ; Liver Neoplasms - secondary ; Lung Neoplasms - secondary ; Mammary gland diseases ; Maximum Tolerated Dose ; Maytansine - administration & dosage ; Maytansine - analogs & derivatives ; Maytansine - pharmacokinetics ; Medical sciences ; Middle Aged ; Neoplasm Staging ; Patient Selection ; Receptor, ErbB-2 - drug effects ; Receptor, ErbB-2 - metabolism ; Risk Assessment ; Survival Analysis ; Thrombocytopenia - chemically induced ; Trastuzumab ; Treatment Outcome ; Tumors
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 3
    Language: English
    In: Nature biotechnology, 2012, Vol.30 (2), p.184-189
    Description: The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione. In contrast, a partially accessible site with a positively charged environment promoted hydrolysis of the succinimide ring in the linker, thereby preventing this exchange reaction. The site with partial solvent-accessibility and neutral charge displayed both properties. In a mouse mammary tumor model, the stability and therapeutic activity of the antibody conjugate were affected positively by succinimide ring hydrolysis and negatively by maleimide exchange with thiol-reactive constituents in plasma. Thus, the chemical and structural dynamics of the conjugation site can influence antibody conjugate performance by modulating the stability of the antibody-linker interface.
    Subject(s): Aminobenzoates - chemistry ; Aminobenzoates - immunology ; Animals ; Antibodies - blood ; Antibodies - chemistry ; Antibodies - immunology ; Antibodies, Monoclonal, Humanized - chemistry ; Antibodies, Monoclonal, Humanized - immunology ; Antibody-drug conjugates ; Binding Sites, Antibody - immunology ; Biological and medical sciences ; Biotechnology ; Biotransformation ; Cell Line, Tumor ; Cell Survival ; Chemical properties ; Cysteine - chemistry ; Fundamental and applied biological sciences. Psychology ; Health. Pharmaceutical industry ; Humans ; Immunoconjugates - administration & dosage ; Immunoconjugates - chemistry ; Immunoconjugates - immunology ; Immunoglobulin G - chemistry ; Immunoglobulin G - immunology ; Industrial applications and implications. Economical aspects ; Macaca fascicularis ; Maleimides - chemistry ; Mammary Neoplasms, Experimental - drug therapy ; Mammary Neoplasms, Experimental - immunology ; Maytansine - chemistry ; Maytansine - immunology ; Mice ; Mice, Nude ; Miscellaneous ; Models, Molecular ; Oligopeptides - chemistry ; Oligopeptides - immunology ; Pharmaceutical biotechnology ; Protein Conformation ; Protein Engineering ; Rats ; Research ; Structure-Activity Relationship ; Sulfhydryl Compounds - chemistry ; Thiols ; Trastuzumab ; Usage
    ISSN: 1087-0156
    E-ISSN: 1546-1696
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 4
    Language: English
    In: Bioconjugate chemistry, 2011-10-19, Vol.22 (10), p.1994-2004
    Description: Antibody–drug conjugates (ADCs) are designed to combine the exquisite specificity of antibodies to target tumor antigens with the cytotoxic potency of chemotherapeutic drugs. In addition to the general chemical stability of the linker, a thorough understanding of the relationship between ADC composition and biological disposition is necessary to ensure that the therapeutic window is not compromised by altered pharmacokinetics (PK), tissue distribution, and/or potential organ toxicity. The six-transmembrane epithelial antigen of prostate 1 (STEAP1) is being pursued as a tumor antigen target. To assess the role of ADC composition in PK, we evaluated plasma and tissue PK profiles in rats, following a single dose, of a humanized anti-STEAP1 IgG1 antibody, a thio-anti-STEAP1 (ThioMab) variant, and two corresponding thioether-linked monomethylauristatin E (MMAE) drug conjugates modified through interchain disulfide cysteine residues (ADC) and engineered cysteines (TDC), respectively. Plasma PK of total antibody measured by enzyme-linked immunosorbent assay (ELISA) revealed ∼45% faster clearance for the ADC relative to the parent antibody, but no apparent difference in clearance between the TDC and unconjugated parent ThioMab. Total antibody clearances of the two unconjugated antibodies were similar, suggesting minimal effects on PK from cysteine mutation. An ELISA specific for MMAE-conjugated antibody indicated that the ADC cleared more rapidly than the TDC, but total antibody ELISA showed comparable clearance for the two drug conjugates. Furthermore, consistent with relative drug load, the ADC had a greater magnitude of drug deconjugation than the TDC in terms of free plasma MMAE levels. Antibody conjugation had a noticeable, albeit minor, impact on tissue distribution with a general trend toward increased hepatic uptake and reduced levels in other highly vascularized organs. Liver uptakes of ADC and TDC at 5 days postinjection were 2-fold and 1.3-fold higher, respectively, relative to the unmodified antibodies. Taken together, these results indicate that the degree of overall structural modification in anti-STEAP1-MMAE conjugates has a corresponding level of impact on both PK and tissue distribution.
    Subject(s): Animals ; Antibodies, Monoclonal - blood ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - pharmacokinetics ; Antigens, Neoplasm - immunology ; Disulfides - chemistry ; Humans ; Immunoconjugates - blood ; Immunoconjugates - chemistry ; Immunoconjugates - pharmacokinetics ; Male ; Models, Molecular ; Oligopeptides - blood ; Oligopeptides - chemistry ; Oligopeptides - pharmacokinetics ; Oxidoreductases - immunology ; Rats ; Rats, Sprague-Dawley ; Tissue Distribution
    ISSN: 1043-1802
    E-ISSN: 1520-4812
    Source: Hellenic Academic Libraries Link
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  • 5
    Language: English
    In: Drug development research, 2014-05, Vol.75 (3), p.115-161
    Description: Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early‐to‐late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi‐functional properties, high potency, long half‐life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off‐target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life‐threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child‐bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune‐mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune‐complex‐mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first‐in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH‐enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented.
    Subject(s): Animals ; Anti-Inflammatory Agents - adverse effects ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal - therapeutic use ; Autoimmunity ; cancer ; Drug Evaluation, Preclinical - methods ; Health aspects ; Humans ; Immunologic Factors - adverse effects ; Immunologic Factors - pharmacology ; Immunologic Factors - therapeutic use ; immunosuppression ; Immunotherapy ; infection ; inflammation ; Inflammation - drug therapy ; Monoclonal antibodies ; monoclonal antibody ; nonclinical safety ; reproductive toxicity ; Safety and security measures
    ISSN: 0272-4391
    E-ISSN: 1098-2299
    Source: Hellenic Academic Libraries Link
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  • 6
    Language: English
    In: Cancer chemotherapy and pharmacology, 2014-09-04, Vol.74 (5), p.969-980
    Description: Purpose Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) comprised of trastuzumab linked to the antimitotic agent DM1, has shown promising results in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Investigations of the mechanisms of the action of ADCs, including T-DM1, have been primarily descriptive or semiquantitative. However, quantitative pharmacokinetic/pharmacodynamic (PK/PD) analysis may provide insights into their complex behavior. The analyses described herein applied PK/PD modeling to nonclinical studies of maytansinoid conjugates. Methods The maytansinoid conjugates T-DM1 and T-SPP-DM1, with thioether and disulfide linkers, respectively, were tested in mouse efficacy, PK, and tumor uptake studies. 3 [H]DM1-bearing ADCs were used to facilitate the quantitation of the ADCs in plasma, as well as ADC and ADC catabolites in tumors. Three mechanistic PK/PD models were used to characterize plasma ADC, tumor ADC, and tumor catabolite concentrations. Tumor catabolite concentrations were used to fit tumor response. Model parameters were estimated using R software and nonlinear least squares regression. Results Plasma ADC-associated DM1 concentrations of T-DM1 decreased more slowly than those of T-SPP-DM1, likely due to slower DM1 release. A comparison of the mechanistic models found that the best model allowed catabolism and catabolite exit rates to differ between ADCs, that T-DM1 exhibited both faster tumor catabolism and catabolite exit rate from tumors than T-SPP-DM1; findings inconsistent with expected behavior based on the physicochemical nature of the respective catabolites. Tumor catabolite concentrations adequately described tumor response with both ADCs showing similar potency. Conclusion Mechanistic PK/PD studies described herein provided results that confirmed and challenged current hypotheses, and suggested new areas of investigation.
    Subject(s): Algorithms ; Analysis ; Animals ; Antibodies, Monoclonal, Humanized - blood ; Antibodies, Monoclonal, Humanized - pharmacokinetics ; Antibody–drug conjugate ; Antimitotic agents ; Antineoplastic agents ; Area Under Curve ; Biological and medical sciences ; Biological products ; Cancer Research ; Cell Line, Tumor ; Female ; Humans ; Maytansine - analogs & derivatives ; Maytansine - blood ; Maytansine - pharmacokinetics ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice, Nude ; Models, Biological ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Oncology ; Original Article ; Pharmacokinetics/pharmacodynamics ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; T-DM1 ; Target cell catabolism ; Trastuzumab ; Trastuzumab emtansine ; Treatment Outcome ; Tritium ; Tumors
    ISSN: 0344-5704
    E-ISSN: 1432-0843
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Journal of pharmacokinetics and pharmacodynamics, 2010-04-28, Vol.37 (3), p.221-242
    Description: Trastuzumab-DM1 (T-DM1) is a novel antibody–drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time–dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.
    Subject(s): Analysis ; Animals ; Antibodies ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal, Humanized ; Antibody–drug conjugate ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Article ; Biochemistry ; Biochemistry, general ; Biomedical and Life Sciences ; Biomedical Engineering ; Biomedical Engineering and Bioengineering ; Biomedicine ; Biopharmaceutics ; Breast cancer ; Cancer ; Care and treatment ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Epidermal growth factor ; Female ; general ; Humans ; Immunotoxins - therapeutic use ; Maytansine - administration & dosage ; Maytansine - analogs & derivatives ; Maytansine - pharmacokinetics ; Metastasis ; Mice ; Mice, Nude ; Models ; Models, Biological ; Mouse ; Neoplasms - drug therapy ; Oncology, Experimental ; Pharmacokinetic/pharmacodynamic modeling ; Pharmacology/Toxicology ; Pharmacy ; Research ; Time Factors ; Trastuzumab ; Treatment regimen determination ; Veterinary Medicine ; Veterinary Medicine/Veterinary Science ; Viral antibodies ; Xenograft Model Antitumor Assays
    ISSN: 1567-567X
    E-ISSN: 1573-8744
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: The AAPS journal, 2017-08-14, Vol.19 (6), p.1715-1734
    Description: ABSTRACT Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1-containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs.
    Subject(s): ADC ; Analysis ; Antibodies ; antibody-drug conjugate ; Biochemistry ; Biochemistry, general ; Biomedical and Life Sciences ; Biomedicine ; Biopharmaceutics ; Biotechnology ; Case studies ; general ; PBPK model ; Pharmacology/Toxicology ; Pharmacy ; physiologically based pharmacokinetic ; preclinical-to-clinical translation ; Research Article ; T-DM1 ; Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates ; Viral antibodies
    ISSN: 1550-7416
    E-ISSN: 1550-7416
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: mAbs, 2016-02-17, Vol.8 (2), p.229-245
    Description: Protein therapeutics represent a diverse array of biologics including antibodies, fusion proteins, and therapeutic replacement enzymes. Since their inception, they have revolutionized the treatment of a wide range of diseases including respiratory, vascular, autoimmune, inflammatory, infectious, and neurodegenerative diseases, as well as cancer. While in vivo pharmacokinetic, pharmacodynamic, and efficacy studies are routinely carried out for protein therapeutics, studies that identify key factors governing their absorption, distribution, metabolism, and excretion (ADME) properties have not been fully investigated. Thorough characterization and in-depth study of their ADME properties are critical in order to support drug discovery and development processes for the production of safer and more effective biotherapeutics. In this review, we discuss the main factors affecting the ADME characteristics of these large macromolecular therapies. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of recombinant biotherapeutic drugs, and demonstrate how ADME studies will facilitate their future development.
    Subject(s): Absorption ; Animals ; Antibodies, Monoclonal - pharmacokinetics ; Antibodies, Monoclonal - therapeutic use ; antibody-drug conjugate (ADC) ; biologics ; biotherapeutics ; distribution ; Drug Discovery - methods ; excretion ; Humans ; imaging ; labeling ; metabolism ; monoclonal antibody (mAb) ; neonatal Fc receptor (FcRn) ; pharmacokinetics ; Review ; subcutaneous bioavailability
    ISSN: 1942-0862
    E-ISSN: 1942-0870
    Source: Taylor & Francis Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    In: Molecular cancer therapeutics, 2012-05, Vol.11 (5), p.1133-1142
    Description: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody-drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the in vitro and in vivo activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examined. Both ADCs showed high in vitro potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. In vitro target cell processing of T-DM1 and T-SPP-DM1 produced lysine-N(ε)-MCC-DM1, and lysine-N(ε)-SPP-DM1 and DM1, respectively; in vivo studies confirmed these results. The in vitro processing rates for the two conjugate to their respective catabolites were similar. In vivo, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concentrations (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chemical nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor.
    Subject(s): Animals ; Antibodies, Monoclonal, Humanized - chemistry ; Antibodies, Monoclonal, Humanized - metabolism ; Antibodies, Monoclonal, Humanized - pharmacokinetics ; Antibodies, Monoclonal, Humanized - pharmacology ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Breast Neoplasms - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; Female ; Humans ; Maytansine - analogs & derivatives ; Maytansine - chemistry ; Maytansine - metabolism ; Maytansine - pharmacokinetics ; Maytansine - pharmacology ; Mice ; Mice, Nude ; Receptor, ErbB-2 - metabolism ; Trastuzumab ; Xenograft Model Antitumor Assays
    ISSN: 1535-7163
    E-ISSN: 1538-8514
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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