Document text
Principal Investigator: Patricia Manuela Ribeiro Pereira
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $601,992
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT – The incidence of gastric and breast cancers is increasing rapidly, rating
fourth and fifth leading causes of cancer mortality worldwide. In patients clinically classified as HER2-positive
(ERBB2 amplification and/or 2+/3+ protein overexpression by immunohistochemistry), antibody-drug conjugates
(ADC) prolong progression-free and overall survival. However, these therapies have low activity in HER2-low
cancer cells, and not all HER2-positive tumors benefit, or even those who initially respond inevitably develop
resistance over time. Guided by preclinical data we obtained in HER2 heterogeneous patient-derived xenografts
demonstrating that an increase in HER-ADC endocytosis enhances therapeutic efficacy, we developed
approaches of antibody delivery that result in a 15.5-fold increase of ADC internalization in cancer cells. Our
novel approach uses pertuzumab and trastuzumab-drug antibodies that click at the surface of cancer cells upon
binding distinct HER2 domains to increase the number of HER2-ADC complexes and further enhance the rate
of HER2-ADC endocytosis. Antibody-PET imaging studies that we have generated demonstrate that our
approach increases the uptake of 89Zr-ADC in heterogeneous tumors containing HER2-high and HER2-low
cancer cells. Here, we will optimize clickable pairs of two epitope-distinct antibody-ADC biomolecules to enhance
tumor targeting and drug delivery in resistant models of breast and gastric cancer. In addition to test the potential
of our approach in cancer cell lines and organoids, we will perform randomized imaging and therapeutic studies
in patient-derived breast and gastric xenografts representing three tumor populations: ADC-eligible tumors of
HER2 heterogeneity, ADC-ineligible tumors, and ADC-resistant tumors. We will determine the molecular imaging
(89Zr-Antibody PET), safety, pharmacokinetic profile, and therapeutic efficacy of ADC alone (no-click) versus
ADC plus pertuzumab conjugated with clicking pairs (click). These randomized preclinical studies will allow us
to identify molecular features that confer drug sensitivity or resistance to this promising investigational approach.
Aim 1 will optimize pertuzumab/ADC clicking pairs with improved tumor uptake and drug delivery when compared
with ADC monotherapies and Aim 2 will validate the use of antibody clicking pairs as a new therapeutic approach.
The two aims will provide important new preclinical data on the use of antibody clicking pairs to enhance drug
delivery, which could provide an excellent foundation for many future investigations, including the clinical
translation of using clicking pairs to enhance drug delivery and the potential broader application to other
membrane receptors and heterogeneous tumors. The long-term translational objectives of the studies proposed
are to establish a foundation for a clinical trial using antibody clicking to prevent or delay drug resistance in
patients with heterogeneous breast and gastric cancers.
Terms: <Affinity><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Antibody Binding Sites><Antibody Therapy><Antibody-drug conjugates><Antigenic Determinants><Binding><Binding Determinants><Biodistribution><Body Tissues><Breast><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Neoplasms><Breast Tumors><Breast tumor model><Cancer Cause><Cancer Etiology><Cancer cell line><Cancers><Cell surface><Classification><Clinical><Clinical Trials><Complex><Copper><Cu element><Cyclooctenes><Data><Dimerization><Disease><Disease Progression><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Therapy><Drug resistance><Drugs><ERBB2><ERBB2 gene><Effectiveness><Eligibility><Eligibility Determination><Endocytosis><Epitopes><Foundations><Future><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Neoplasms><Gastric Pylorus Cancer><Gastric Tumor><Genetic Alteration><Genetic Change><Genetic defect><Goals><HER -2><HER-2><HER2><HER2 Genes><HER2 Monoclonal Antibody><HER2/neu><Herceptin><Heterogeneity><Heterograft><Heterologous Transplantation><Human><Image><Imaging technology><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Incidence><Intratumoral heterogeneity><Investigation><Label><Malignant Breast Neoplasm><Malignant Cell><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Medical><Medication><Membrane><Methodology><MoAb HER2><Modern Man><Molecular><Molecular Interaction><Monitor><Mutation><NEU Oncogene><NEU protein><Oncogene ErbB2><Oncogenic><Organoids><PDX model><PET><PET Scan><PET imaging><PETSCAN><PETT><PTK Receptors><Paratopes><Pathway interactions><Patient Care><Patient Care Delivery><Patient derived xenograft><Patients><Pertuzumab><Pharmaceutical Preparations><Pharmacokinetics><Pharmacotherapy><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Pre-Clinical Model><Preclinical Models><Predisposition><Protein Dimerization><Protein Overexpression><Proteins><Protocol Screening><Rad.-PET><Randomized><Reaction><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Refractory><Resistance><Resistance development><Resistant development><Safety><Scheme><Signal Pathway><Site><Stomach><Stomach Cancer><Stomach Neoplasms><Stomach Tumor><Surface><Susceptibility><Systematics><TKR1><Testing><Therapeutic><Therapeutic Studies><Therapy Research><Time><Tissues><Toxic effect><Toxicities><Translations><Transmembrane Receptor Protein Tyrosine Kinase><Trastuzumab><Treatment Efficacy><Treatment outcome><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Xenograft><Xenograft procedure><Xenotransplantation><antibody based therapies><antibody combining site><antibody treatment><antibody-based therapeutics><antibody-based treatment><breast tumor cell><c-erb-2 Monoclonal Antibody><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><care for patients><care of patients><caring for patients><clinical translation><clinically translatable><crosslink><cytotoxic><developing resistance><dosimetry><drug resistant><drug sensitivity><drug treatment><drug/agent><effective therapy><effective treatment><erbB-2 Genes><extracellular><gastric><gastric cancer cell><gastric malignancy><genome mutation><herstatin><heterogeneity in tumors><imaging><imaging study><improved><improved outcome><intervention efficacy><intra-tumoral heterogeneity><intratumor heterogeneity><malignancy><malignant breast tumor><malignant stomach neoplasm><malignant stomach tumor><mammary cancer model><mammary tumor><mammary tumor model><membrane structure><molecular imaging><molecule imaging><mortality><neoplasm/cancer><neu Genes><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathway><patient derived xenograft model><permissiveness><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><randomisation><randomization><randomly assigned><receptor><resistance mechanism><resistance to Drug><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to therapy><response><response to therapy><response to treatment><rhuMAb HER2><rhuMAb2C4><site targeted delivery><standard of care><stomach fundus cancer><stomach pylorus cancer><targeted delivery><therapeutic efficacy><therapeutic resistance><therapeutic response><therapeutically effective><therapy efficacy><therapy resistant><therapy response><trafficking><translation><treatment resistance><treatment response><treatment responsiveness><tumor><tumor heterogeneity><uptake><xeno-transplant><xeno-transplantation>