Novel Antigen-Binding Constructs in Colorectal Cancer

A33是一种与结肠癌结合的抗体，它的抗原结合结构已经优化。 无免疫原性；保留抗原结合能力，并更快地清除非肿瘤部位。当前 基于免疫球蛋白的结肠癌和其他实体肿瘤的治疗受到低肿瘤非肿瘤的限制 比率。我们已作出努力，通过a)增加血清清除量来提高这一比例；b) 增加抗原结合结构的肿瘤穿透性，以及c)发展双特异性抗原结合 识别肿瘤抗原的结构和可以携带放射性核素的螯合物。 这项资助旨在研究两种抗原结合结构：单链抗体(SFV)片段和融合 由SFV A33和抗螯合物(DOTA)的SFV组成的蛋白质。临床试验将在#年进行。 可测量疾病的患者：对计划接受疾病活检的患者进行的初步试验， 随后是使用正电子发射放射金属和系列PET成像的试验。这些研究将会有所帮助 为随后的放射免疫治疗确定最佳的抗原结合结构。 特异性靶向1将确定SFV A33的肿瘤靶向性和最佳给药途径 可测量的转移性结肠癌患者。第一项研究将使用IV111ln-DOTA-SFV A33在术前 转移性结肠癌患者；如果这项研究表明目标是正常结肠癌和/或 对于肿瘤，我们将与动脉内111ln-DOTA-SFV A33进行对比研究，以确定是否 给药途径影响靶向。随后将使用86Y-DOTA-SFV A33进行PET研究。 我们正在生产一种由两个SFV分子组成的双特异性抗原结合结构： 一个SFV以A33抗原为靶标，而另一个SFV与金属偶联的DOTA螯合物反应。 特定目标2将确定该构建物的最佳给药途径和靶向，临床应用 试验设计与具体目标1相似。 特异靶向3将评估使用PET的肿瘤靶向性，以及新型人源化A33抗体的免疫原性。 这些研究将形成研究的模板，以确定SFV A33在检测和 结肠癌的治疗；双特异性结构在结肠癌检测和治疗中的应用； 以及一种新的非免疫原性A33免疫球蛋白特异性靶向结肠癌的能力。

Optimized antigen-binding constructs of A33, an antibody that binds to colon cancer, have been engineered to be non-immunogenic; retain antigen-binding ability, and clear faster from non-tumor sites. Current immunoglobulin-based therapy of colon cancer as well as other solid tumors is limited by low tumornontumor ratios. We have undertaken an effort to increase this ratio by a) increasing serum clearance; b) increasing tumor penetrance of antigen-binding construct, and c) developing bispecific antigen-binding constructs that recognize tumor antigen and chelates that can carry radionuclides. This grant aims to study two antigen-binding constructs: a single chain Fv (sFv) fragment, and a fusion protein consisting of sFv A33 and a sFv against a chelate (DOTA). The clinical trials will be carried out in patients with measurable disease: the initial trials in patients scheduled to undergo biopsy of their disease, followed by trials using positron-emitting radiometals and serial PET imaging. These studies will help determine the optimum antigen-binding construct for subsequent radioimmunotherapy. Specific Aim 1 will determine the tumor targeting abilities and optimum route of administration of sFv A33 in patients with measurable metastatic colon cancer. The first study will be with IV 111ln-DOTA-sFv A33 in presurgical patients with metastatic colon cancer; if this study demonstrates targeting to normal colon and/or tumor, we will carry out a comparable study with intra-arterial 111ln-DOTA-sFv A33, to determine whether route of administration influences targeting. These will be followed by a PET study with 86Y-DOTA-sFv A33. We are in the process of producing a bispecific antigen-binding construct consisting of 2 sFv molecules: one sFv targets the A33 antigen while the other sFv reacts with metal-conjugated DOTA chelate. Specific Aim 2 will determine the optimal route of administration and targeting of this construct, with clinical trial design being similar to that in Specific Aim 1. Specific Aim 3 will evaluate tumor targeting using PET, and immunogenicity of a novel humanized A33 IgG. These studies will form the template for studies to determine the utility of sFv A33 in the detection and treatment of colon cancer; the utility of bispecific constructs in the detection and treatment of colon cancer; and the ability of a novel non-immunogenic A33 IgG to specifically target colon cancer.