The use of tMUC1/CD3 bispecific antibody to control pancreatic ductal adenocarcinoma

双特异性抗体(BsAbs)是一种新兴的癌症免疫治疗策略，可重新启动免疫效应器 从而促进免疫突触的形成，诱导肿瘤细胞溶解。BsAbs目标 同时检测肿瘤相关抗原(TAA)和效应细胞抗原。BsAbs治疗的成功 这在很大程度上取决于识别TAA和高度特异的TAA靶向抗体。胰腺癌有 是所有癌症中预后最差的。如果在手术切除肿瘤的早期阶段就发现了癌症 有可能，5年存活率为34%。大约10%的人在这个阶段被诊断出来。如果癌症有 扩散至周围组织或器官，5年存活率为12%。对于52%的人来说 在癌症扩散到身体的远处后被诊断出来，5年存活率为3%。在2020年，它是 估计将有57 600例新病例(30 400名男性和27 200名女性)和47 050人因此而死亡 美国的疾病。平均预期寿命不到6个月，长期存活的人很少。 胰腺浸润性导管腺癌(PDA)占胰腺外分泌物的95%以上 恶性肿瘤。MUC1(CD227)是一种膜栓系的粘蛋白糖蛋白，表达于牙周炎的根尖表面。 正常的腺上皮细胞，但在80%的人PDA中过度表达和异常糖基化。肿瘤 已知相关MUC1(TMUC1)与癌细胞的转移表型有关。这个 NCI将tMUC1确定为第二好的免疫治疗靶点。最近与 在Dualogics LLC的基础上，我们成功地开发了几种新型的BsAbs，它能将tMUC1结合到肿瘤细胞上，并 T效应细胞表面CD3的表达。这些BsAb对三阴性乳腺癌细胞显示出治疗效果 体外培养。众所周知，PDA细胞对治疗高度耐药。我们已经证明了内在的 PDA细胞中的免疫检查点因素，如吲哚胺2，3双加氧酶(IDO1)，在一定程度上解释了 PDA对我们的嵌合抗原受体(CAR)工程T细胞介导的杀伤的抵抗力。此外，我们 还显示，次佳剂量的化疗药物，如5-氟尿嘧啶、吉西他滨和紫杉醇 能打破对PDA的抵抗，与CAR T细胞协同杀伤PDA细胞。因此，我们 假设PDA可以与tMUC1/CD3双特异性抗体MUCD3特异性靶向。 MUCD3联合IDO1抑制剂(1mT)或常规化疗将增强抗肿瘤作用 MUCD3的疗效。特异性目的是证明MUCD3介导的人PDA体外肿瘤杀伤作用 并在体内以适当的模型进行组合和不组合。成功后，它将提供一个新的 针对tMUC1表达实体瘤的肿瘤免疫治疗的有效模式。

Bispecific antibodies (BsAbs) are an emerging cancer immunotherapy strategy to re-engage immune effectors with tumor cells thus to promote immune synapse formation and induce tumor cytolysis. The BsAbs target tumor associated antigen (TAA) and effector cell antigen simultaneously. The success of BsAbs therapy largely relies on identifying TAA and the highly specific TAA-targeting antibodies. Pancreatic cancer has the worst prognosis of all cancers. If the cancer is detected at an early stage when surgical removal of the tumor is possible, the 5-year survival rate is 34%. About 10% of people are diagnosed at this stage. If the cancer has spread to surrounding tissues or organs, the 5-year survival rate is 12%. For the 52% of people who are diagnosed after the cancer has spread to a distant part of the body, the 5-year survival rate is 3%. In 2020, it is estimated that there will be 57,600 new cases (30,400 men and 27,200 women) and 47,050 deaths due to this disease in the US. The mean expectation of life is less than six months and there are few long-term survivors. Infiltrating ductal adenocarcinoma of the pancreas (PDA) accounts for over 95% of all exocrine pancreatic malignancies. MUC1 (CD227) is a membrane tethered mucin glycoprotein expressed on the apical surfaces of normal glandular epithelia but is overexpressed and aberrantly glycosylated in >80% of human PDA. Tumor associated MUC1 (tMUC1) is known to be associated with the metastatic phenotype of cancer cells. The tMUC1 is identified as the second best target for immunotherapy by NCI. Recently in collaboration with Dualogics LLC, we have successfully developed several novel BsAbs which bind tMUC1 on tumor cells and CD3 on T effector cells. Those BsAbs show therapeutic efficacy against triple negative breast cancer cells in vitro. PDA cells have been known to be highly refractory to treatments. We have demonstrated that the intrinsic immune checkpoint factors in the PDA cells such as indoleamine 2, 3 dioxygenase (IDO1) partially account for the PDA resistance to our chimeric antigen receptor (CAR) engineered T cell-mediated killing. Furthermore, we also showed that suboptimal doses of chemotherapy drugs like 5-fluorouracil, Gemcitabine, and Paclitaxel could break down the PDA resistance and synergize with CAR T cells for PDA cytolysis. Therefore, we hypothesize that PDA can be specifically targeted with the tMUC1/CD3 bispecific antibody, MUCD3. Combining MUCD3 with IDO1 inhibitor (1MT) or standard-of-care chemotherapy will enhance the anti-tumor efficacy of MUCD3. Specific aims are to demonstrate MUCD3 mediated tumor killing of human PDA in vitro and in vivo in the appropriate models with and without combinations. When successful, it will provide a new effective modality for cancer immunotherapy targeting at tMUC1-expressing solid tumors.