ABTELUM BIOMEDICAL, INC. aims to advance a humanized anti-DEspR neutralizing antibody, ABT-468, with a stabilized IgG4/kappa framework, as a potential first-in class therapy for pancreatic adenoductal carcinoma (PDAC), with the worst prognosis among all cancers. To advance IND-enabling experiments for ABT-468, this SBIR-Phase I tests the therapeutic hypothesis that ABT-468 will inhibit metastatic progression and increase overall survival â relevant to Stage IV PDAC patients and resected PDAC patients. We propose testing ABT-468 in the biological context of pancreatic peritoneal metastasis (PPM) in order to stringently test efficacy and gain insight into its safety in the biological context of the worst of PDAC metastases, and in the presence of its debilitating co-morbidities. We project that this preclinical approach will be more predictive of clinical trial efficacy. DEspR is a clinically relevant target with a unique multi-pronged mechanism of action. DEspR is induced in 94% of PDAC patient tumors tested (n=133), in primary and metastatic tumors, in all stages and both sexes. ABT-468 targets and inhibits key metastasis drivers: a) cancer stem-like cells (CSCs) â resulting in decreased CSC survival, anoikis resistance and self-renewal required for metastatic dissemination and seeding, b) angiogenic endothelial cells (angECs) â resulting in inhibition of angiogenesis required for metastatic tumor outgrowth beyond 1-2 mm, and maintenance of CSC-niche integrity, and in c) activated neutrophils (actPMNs) â resulting in decreased survival thus eliminating actPMN roles in tumor cell invasiveness and immune-evasion. Moreover, as DEspR is minimally present in normal tissues, ABT-468 has an inherent mechanism for safety, with no chemotherapy-like toxicities or adverse events. These advantages are supported by experimental evidence and multiple patent applications, with US Patent #7,919,093 issued 04/05/2011. ABT-468, our lead among 5 other candidates, exhibits improved binding and functional activity compared to its murine precursor mAb. To advance IND- enabling experiments, we propose the following aims. Aim 1. Towards IND filing, we will test A) whether ABT-468 dose-dependently increases overall survival better than the standard of care gemcitabine and placebo controls, and B) whether DEspR mechanism-based biomarkers correlate with treatment response, to facilitate translation to the clinic. Survival-efficacy studies will be done in two CSC-derived xenograft (CDX) PPM nude rat models in both sexes. Aim 2. Towards IND filing, we will study anti-DEspR ABT-468 mechanism of action in vivo by A) elucidating its target engagement on tumor cells, microvessels, and neutrophils in advanced stage primary PDAC+PPM tumors, and B) by determining the tumor bioeffects on induction of apoptosis in invasive and bulk tumor cells as expected from ABT-468's mechanism of action, in contrast to isotype control. Impact. Completion of aims will attain IND-enabling experiments to advance ABT-468 as a novel therapy for PDAC with no chemotherapy-like toxicities and for other cancers as well.
Public Health Relevance Statement: This research aims to advance the translation to the clinic of a potential first-in-class fully humanized anti- DEspR antibody, ABT-468, as novel cancer therapy with a three-pronged mechanism of action which inhibits key players in metastasis: cancer stem cells (CSC), tumor blood vessel formation, and activated neutrophils which promote tumor cell invasiveness and immune-evasion. We propose to rigorously test ABT-468 in a CSC-derived xenograft tumor model pancreatic peritoneal metastasis, which has no curative- intent therapy. Completion of this SBIR Phase I will attain key milestones towards IND-filing for ABT-468, in order to advance translation to the clinic for PDAC, and in future, therapy for other metastatic cancers.
Project Terms: Address; Adjuvant Chemotherapy; Adjuvant Therapy; Adverse event; Affinity; angiogenesis; Angiogenesis Inhibition; Anoikis; Antibodies; Apoptosis; Ascites; Avastin; base; Biliary; Binding; Biological; Biological Markers; Blinded; blood vessel development; Cachexia; cancer stem cell; cancer therapy; Carcinoma; Carcinomatosis; Cell surface; Cell Survival; Cells; chemotherapy; Clinic; Clinical; clinical predictors; clinical translation; clinically relevant; Colon; Colon Carcinoma; Combined Modality Therapy; Comorbidity; Complex; Data; Detection; Disseminated Malignant Neoplasm; Dose; Duct (organ) structure; Early treatment; efficacy study; efficacy testing; efficacy trial; Endothelial Cells; Exhibits; exosome; experimental study; Female; Future; gemcitabine; Goals; Hematogenous; Hepatic; Hour; Human; Icterus; IgG4; Immune Evasion; improved; in vivo; Induction of Apoptosis; insight; Ischemia; Lead; Legal patent; Link; live cell imaging; Lymphocyte; Maintenance; male; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant Neoplasms; Measurement; Membrane; Modeling; Molecular; Monoclonal Antibodies; mouse model; murine monoclonal antibody; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; neoplastic cell; neutralizing antibody; Neutropenia; neutrophil; new therapeutic target; Normal tissue morphology; novel; novel therapeutics; Nude Rats; Obstruction; Operative Surgical Procedures; outcome forecast; Pancreas; pancreas xenograft; Pancreatic carcinoma; Patients; Peritoneal; Phase; phase 1 testing; Placebo Control; Placebos; pre-clinical; prevent; Prevention; Primary Neoplasm; Rattus; receptor; Research; Resected; Resistance; response; Role; Safety; self-renewal; Severities; sex; Signal Transduction; Site; Small Business Innovation Research Grant; Solid Neoplasm; standard of care; Statistical Data Interpretation; stem-like cell; Stomach; Surrogate Markers; targeted treatment; Testing; therapeutic evaluation; Toxic effect; Translations; Treatment Failure; treatment response; tumor; Tumor Debulking; tumor growth; tumor xenograft; Tumor-Derived; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft pr
