SBIR Topic 255: Evaluate Therapeutic Potential of Novel Immunomodulator, Imprime

胰腺癌是一种罕见的法塔L病，治疗方案很少。目前，有希望的抗肿瘤策略使用联合疗法，每种药物针对肿瘤发生的不同方面。令人失望的是，抗EGFR单抗(MAb)西妥昔单抗与标准护理方案吉西他滨联合使用，未能提高这种疾病的存活率。虽然EGFR在胰腺癌中过度表达，但90%的胰腺癌也含有KRAS突变。我们在此提出了一种策略，可以克服KRAS突变对抗EGFR单抗的耐药性。Bithera正在开发ImPrime-PGG？，一种β1，3/1，6葡萄糖聚合物，作为单抗的辅助药物用于癌症治疗。专利药物IMPRIME可诱导中性粒细胞介导的细胞毒作用，使中性粒细胞(占人类免疫细胞的-50%-70%)识别和杀伤MAb靶向肿瘤。临床前，IMPRIME已在多种肿瘤模型中显示出作为单抗的辅助治疗效果，包括KRAS突变的肺癌和结肠癌模型。再加上1b/2期转移性结直肠癌研究的安全性和最新疗效数据，支持将其作为一种安全有效的药物。总体目标是在胰腺癌移植瘤中建立这种新的治疗方法的临床前概念验证；KRAS野生型和KRAS突变肿瘤将被研究，并随后在临床上评估治疗潜力。

Pancreatic cancer is a "rare" and fata l disease, with few treatment options. Currently, promising antitumor strategies utilize combination therapies, with each agent targeting separate aspects of oncogenesis. Disappointingly, combination of anti- EGFR monoclonal antibody (MAb), cetuximab, with standard-of-care, gemcitabine, failed to improve survival in this disease. Although EGFR is over-expressed in >90% of pancreatic carcinomas -90% also contain KRAS mutations. We herein propose a strategy that could overcome resistance of KRAS mutations to anti-EGFR MAbs. Biothera is developing Imprime-PGG¿, a beta 1,3/1,6 glucose polymer, as an adjunct to MAbs for cancer treatment. The proprietary agent, Imprime, induces neutrophil-mediated cellular cytotoxicity, where Imprime 'primes' neutrophils (comprise -50%-70% of human immune cells) to recognize and kill MAb targeted tumors. Preclinically, Imprime has shown therapeutic efficacy as an adjunct to MAbs in various tumor models, including KRAS-mutated lung and colon carcinoma models. This coupled wi th the safety and recent efficacy data from a Phase 1 b/2 metastatic CRC study supports Imprime to be a safe and effective drug. Overall objective is to establish preclinical proof of concept for this novel treatment approach in pancreatic cancer xenografts; both KRAS-wild type and KRASmutant tumors will be studied, and subsequently evaluate therapeutic potential in the clinic.