Contract Title: SBIR Phase I Topic 324 Development of an Imaging Agent Targeting

糖链抗原唾液酸-刘易斯a(SleA)，又称CA19.9，在胰腺癌中广泛表达，血清CA19.9的表达可作为胰腺癌的肿瘤标志物。SleA是E-选择素黏附分子的配基，SleA的过度表达可能是肿瘤侵袭转移的关键事件。我们已经制备了一系列全人单抗，并基于对SleA的高亲和力和精致的特异性选择了5b1(IgG1/&955；)用于进一步研究。在SCID小鼠体内的一系列胰腺和其他肿瘤细胞系中显示出显著的疗效。放射性标记的5b1(89Zr-5b1)被证明可以在多种模型中特异性地定位肿瘤，包括皮下和原位PC模型，通过更早和更清晰地成像这些优于FDG-PET，即使在存在高血清CA19.9水平的情况下也是如此。这项建议的具体目的是进行概念验证、临床前研究和初步毒理学研究，长期目标是评估5b1在0/1期临床研究中的效用。

The carbohydrate antigen sialyl-Lewis a (sLea), also known as CA19.9, is widely expressed in pancreatic cancer (PC), and serum CA19.9 expression is used as a tumor marker in PC. sLea serves as a ligand for E-selectin adhesion molecules and over-expression of sLea may be a key event in invasion and metastasis. We have generated a series of fully human monoclonal antibodies (mAb) and 5B1 (IgG1/λ) was selected for further studies based on high affinity and exquisite specificity for sLea. Remarkable in vivo efficacy was demonstrated with a series of pancreatic and other cancer cell lines in SCID mice. Radiolabeled 5B1 (89Zr-5B1) was demonstrated to specifically localize tumors in multiple models, including subcutaneous and orthotopic models of PC, out-performing FDG-PET by imaging these earlier and more clearly, even in the presence of high serum CA19.9 levels. The specific aims for this proposal are to perform proof of concept preclinical studies and preliminary toxicological studies, and the long-term objective is to evaluate 5B1 utility in a Phase 0/1 clinical study.