An Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) for Treating Pancreatic Cancer

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Abstract 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.