Cancer is a major cause of morbidity and mortality in the US, with 1.8 million cases and 600 thousand cancerdeaths projected for 2020. Substantial progress in cancer treatment has been made in the past two decades,largely through the development of highly targeted therapies, including development of antibody-drug conjugates(ADCs). ADCs employ monoclonal antibodies with specificity for tumor-associated antigens to increase theefficiency and selectivity of the delivery of anti-cancer toxins (i.e., payloads) to cancer cells. Although thisapproach has proven to be successful, with 8 anti-cancer ADCs approved for use in the US (brentuximab vedotin,trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumabvedotin, trastuzumab deruxtecan, and sacituzumab govitecan), ADC therapies are often associated withsubstantial off-target toxicity, narrow therapeutic windows, and high failure rates in clinical testing. Considerationof the FDA-approved ADCs shows that these agents often allow a modest extension in average survival time,but they very rarely cure a patient from their cancer. The development of adverse events prevents theadministration of ADC at dosages that are necessary to achieve tumor eradication. This project pursues a newstrategy to increase the tumor-selectivity of antibody-directed delivery of anti-cancer drugs. In our approach,payload-binding antibody fragments, termed payload-binding selectivity enhancers (PBSE), are co-administeredwith ADCs to decrease the exposure of healthy tissues to payload agents, thereby reducing the development ofoff-target toxicity, increasing the tolerable dose of ADCs, and increasing ADC efficacy. The strategy is based onthe recognition that off-site ADC toxicity is primarily attributed to the released ("free") payload molecule, and alsoon the hypothesis that PBSE may be employed to prevent cellular entry of free payload molecules in non-targetedcells (by preventing diffusion across plasma membranes) without altering entry of ADCs into targeted cells (whichproceeds via receptor mediated endocytosis). Work on this project focuses on lead optimization for newlydeveloped anti-SN38 PBSE, which are expected to increase the safety and efficacy of SN38 ADC, includingsacituzumab govitecan. The project will develop optimized derivatives of our lead anti-SN38 PBSE, evaluate thePBSE constructs for plasma, tissue, and tumor disposition, and conduct assessments of safety and efficacy inmice bearing human breast cancer xenografts. In sum, work proposed in this Phase 1 project will enable theidentification of an optimized lead anti-SN38 PBSE, which will then advance through IND-enabling preclinicalinvestigations. Narrative
This project develops anti-SN38 antibody fragments for use as an adjunctive therapy to
decrease the toxicity of antibody-SN38 conjugates. The strategy introduced in this proposal, and
the optimized anti-SN38 agent to be developed, may be expected to increase the safety and
efficacy of SN38 antibody-drug conjugates, including sacituzumab govitecan. It is anticipated
that anti-SN38 and sacituzumab govitecan will be used as a combination therapy to treat
patients with metastatic triple-negative breast cancer, which is associated with very poor
prognosis. Albumins ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antineoplastic Agents ; Anti-Cancer Agents ; Antineoplastic Drugs ; Antineoplastics ; Cancer Drug ; Neoplastic Disease Chemotherapeutic Agents ; Tumor-Specific Treatment Agents ; anti-cancer drug ; anticancer agent ; anticancer drug ; Blood Circulation ; Bloodstream ; Circulation ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Buffaloes ; Camptothecin ; 20-(S)-camptothecine ; 22-secocamptothecin-21-oic acid lactone 21 ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell membrane ; Cytoplasmic Membrane ; Plasma Membrane ; plasmalemma ; Cells ; Cell Body ; Clinical Trials ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Cessation of life ; Death ; Diffusion ; Engineering ; Extracellular Fluid ; Half-Life ; Human ; Modern Man ; Hydrolysis ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunoglobulin Fragments ; Antibody Fragments ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Membrane Proteins ; Membrane Protein Gene ; Membrane-Associated Proteins ; Surface Proteins ; Methods ; Morbidity - disease rate ; Morbidity ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; New York ; Legal patent ; Patents ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Safety ; Testing ; Time ; Tissues ; Body Tissues ; Toxin ; Tumor Antigens ; Tumor-Associated Antigen ; cancer antigens ; tumor-specific antigen ; Universities ; Work ; Enhancers ; Life Extension ; base ; dosage ; improved ; Left ; Site ; Clinical ; Diffuse ; premature ; prematurity ; Phase ; Evaluation ; Failure ; Funding ; uptake ; Therapeutic ; Malignant Cell ; cancer cell ; Investigation ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; extracellular ; Lytotoxicity ; cytotoxicity ; receptor mediated endocytosis ; Toxicities ; Toxic effect ; novel ; 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 ; HER2 Monoclonal Antibody ; Herceptin ; MoAb HER2 ; c-erb-2 Monoclonal Antibody ; rhuMAb HER2 ; Trastuzumab ; Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody ; Mylotarg ; gemtuzumab ; hP67.6-Calicheamicin ; Gemtuzumab Ozogamicin ; Adverse Experience ; Adverse event ; Cancer Treatment ; Malignant Neoplasm Therapy ; Malignant Neoplasm Treatment ; anti-cancer therapy ; anticancer therapy ; cancer-directed therapy ; cancer therapy ; Bystander Effect ; Molecular Interaction ; Binding ; pyrrolobenzodiazepine ; preventing ; prevent ; Dose ; Affinity ; human cancer mouse model ; Sum ; in vivo ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Molecular ; Development ; developmental ; pre-clinical ; preclinical ; triple-negative invasive breast carcinoma ; TNBC ; triple-negative breast cancer ; design ; designing ; targeted delivery ; site targeted delivery ; tumor eradication ; clinical application ; clinical applicability ; commercialization ; tumor ; FDA approved ; tumor specificity ; nanobodies ; nanobody ; sdAb ; single domain antibodies ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; Antibody-drug conjugates ; experimental study ; experiment ; experimental research ; lead optimization ; anti-cancer ; anticancer ; safety assessment ; Prognosis ;
