Pancreatic ductal adenocarcinoma (PDAC) ranks the seventh in causing cancer-related death among all human cancers with very poor prognosis and horrendous survival rate. Despite the use of gemcitabine/nab- paclitaxel and FOLFIRINOX, the median survival rates for patients with metastatic PDAC are still less than one year. Immune checkpoint inhibitor had little responses against PDAC in clinical trials. Currently, there is an urgent unmet need to develop precision medicine that can be used for more effective treatment of PDAC. One exciting strategy to specifically kill solid tumors is by using antibody-drug conjugate (ADC), which has achieved remarkable success both clinically and commercially. Unfortunately, the development of ADC for a specific cancer type such as PDAC is significantly limited by the lack of tumor surface antigens that bind only to cancer cells of interest but not normal cells. In this SBIR Phase I project, we propose to develop an Aptamer- directed IgG-Fc Drug Conjugate (AFDC) platform by integrating the unique aptamer highly specific to PDAC cells with the Fc fragment of human IgG1 that is well-known to have prolonged circulating time and exposable cysteine residues for efficient conjugation with cytotoxic warhead. Two specific aims will be pursued. The first aim is to validation of APTPDAC-mediated killing of PDAC cells and development of a potent Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) highly specifically against human PDAC cells. The second aim is to perform in vivo evaluation, assess anti-tumor efficacy of AFDC in orthotopic PDAC mouse models, and identify the putative cell surface receptor(s) on PDAC cells that is recognized by APTPDAC. The success of this proof-of-concept Phase I project will result in an innovative drug conjugate platform with unique features and a drug candidate that can be further developed for the treatment of PDAC. In the Phase II studies, we will perform extensive mechanistic studies on the identified target(s) for tissue specificity and possible side toxicities. We will more accurately determine the drug conjugation sites, the ratios of aptamer, Fc and vcMMAE in the final product by trypsin digest/MOTI-TOF, and trypsin digest/HPLC. The in vivo stability of aptamer can be further enhanced by using the 2'-fully modified RNA aptamer technology the Liu lab reported. We will further engineer additional cysteine residues to the N-terminal region of IgG1-Fc and test the upper limit of drug-to-Fc ratios that can be achieved, to evaluate the consequences in terms of toxicity and therapeutic efficacy in human PDAC PDX mouse models. When we have generated sufficient data in CMC and preclinical studies, we will seek for CRO to generate materials under the GMP regulations and get ready for PK and toxicity studies in dogs and in primates. These studies will pave the road for an IND application for a phase I human clinical trial.
Public Health Relevance Statement: Project Narrative This SBIR Phase I project is directed at developing an innovative precision medicine based on Aptamer- directed IgG1-Fc Drug Conjugate (AFDC) for the treatment of pancreatic cancer.
Project Terms: Animals; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; immunogen; Antigens; Cell Surface Antigens; Immunologic Surface Markers; Immunological Surface Markers; Surface Antigens; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; chemical synthesis; Chemistry; High Pressure Liquid Chromatography; HPLC; High Performance Liquid Chromatography; High Speed Liquid Chromatography; Clinical Research; Clinical Study; Clinical Trials; Cysteine; Half-Cystine; L-Cysteine; Cessation of life; Death; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Flow Cytometry; Flow Cytofluorometries; Flow Cytofluorometry; Flow Microfluorimetry; Flow Microfluorometry; flow cytophotometry; Human; Modern Man; Immunoglobulin G; 7S Gamma Globulin; IgG; IgG1; Fc Immunoglobulins; Fc Fragments; In Vitro; Ketones; Maleimides; Inbred BALB C Mice; BALB C Mouse; BALB/c; Mus; Mice; Mice Mammals; Murine; Neoplasm Metastasis; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Nucleic Acids; Pancreas; Pancreatic; Pathology; Patients; Drug Kinetics; Pharmacokinetics; Primates; Primates Mammals; Cell Surface Receptors; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Specificity; Sulfhydryl Compounds; Mercaptans; Mercapto Compounds; Thiols; sulfhydryl group; Survival Rate; Technology; Testing; Time; Tissues; Body Tissues; Trypsin; Tripcellim; Tumor Antigens; Tumor-Associated Antigen; cancer antigens; tumor-specific antigen; Vascularization; gemcitabine; Difluorodeoxycytidine; dFdC; dFdCyd; Mediating; Anzatax; Asotax; Bristaxol; Paclitaxel (Taxol); Praxel; Taxol; Taxol A; Taxol Konzentrat; Paclitaxel; cancer progression; neoplasm progression; neoplastic progression; tumor progression; Label; Site; Surface; Clinical; Penetration; Phase; Confocal Microscopy; Solid Tumor; Solid Neoplasm; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Therapeutic; Cytotoxic drug; Cytotoxic agent; cancer cell; Malignant Cell; Malignant neoplasm of pancreas; Malignant Pancreatic Neoplasm; Pancreas Cancer; Pancreatic Cancer; pancreatic malignancy; Chemotherapy-Oncologic Procedure; Chemotherapy Protocol; Chemotherapy Regimen; Combination Chemotherapy Regimen; Quimioterapia; cancer chemotherapy; human tissue; Event; Side; Reaction; interest; Services; Cell Proliferation; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; interstitial; neoplastic cell; Tumor Cell; receptor; Receptor Protein; success; transamination; aptamer; Toxic effect; Toxicities; Reporting; Bypass; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Regulation; response; Proteomics; antigen bound; antigen binding; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Normal Cell; Tissue Sample; Pancreatic Ductal Adenocarcinoma; Pancreas Ductal Adenocarcinoma; Aptamer Technology; cytotoxic; Data; Quantitative Reverse Transcriptase PCR; Quantitative RTPCR; qRTPCR; Recombinants; Reproducibility; in vivo; Apoptotic; Cancer Etiology; Cancer Cause; Scheme; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; validations; Process; Derivation procedure; Derivation; Development; developmental; preclinical study; pre-clinical study; next generation; nano particle; nano-sized particle; nanosized particle; nanoparticle; Biodistribution; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; cancer type; NH2-terminal; N-terminal; Homing; innovate; innovative; innovation; murine model; mouse model; tumor; FDA approved; effective treatment; effective therapy; product development; drug candidate; pancreatic tumor cells; pancreatic cancer cells; phase II study; phase 2 study; biophysical characteristics; biophysical characterization; biophysical measurement; biophysical parameters; biophysical properties; precision-based medicine; precision medicine; Antibody-drug conjugates; efficacy study; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; in vivo testing; in vivo evaluation; anticancer; anti-cancer; PDAC cancer cell; PDAC cell; pancreatic ductal adenocarcinoma cell; Prognosis; manufacturing cost; fabrication cost; technology platform; technology system
