Novel Antigen-Binding Constructs in Colorectal Cancer

已经工程化了A33（一种结合结肠癌的抗体）的优化抗原结合构建体， 无免疫原性;保留抗原结合能力，并更快地从非肿瘤部位清除。电流 结肠癌和其他实体瘤的基于免疫球蛋白的治疗受到低肿瘤非肿瘤的限制， 比率。我们已通过a）增加血清清除率; B） 增加抗原结合构建体的肿瘤转移率，和c）开发双特异性抗原结合 识别肿瘤抗原的构建体和可携带放射性核素的螯合物。 该基金旨在研究两种抗原结合结构：单链抗体（sFv）片段和融合抗体。 由sFv A33和针对螯合物的sFv（DOTA）组成的蛋白质。临床试验将在 患有可测量疾病的患者：在计划对其疾病进行活检的患者中进行的初始试验， 随后是使用正电子发射放射性金属和连续PET成像的试验。这些研究将有助于 确定用于后续放射免疫治疗的最佳抗原结合构建体。 特异性目标1将确定sFv A33在肿瘤中的靶向能力和最佳施用途径。 患有可测量的转移性结肠癌的患者。第一项研究将是在手术前使用IV 111 In-DOTA-sFv A33。 转移性结肠癌患者;如果本研究证明靶向正常结肠和/或 我们将用动脉内111 In-DOTA-sFv A33进行一项可比较的研究，以确定是否 给药途径影响靶向。这些之后将是用86 Y-DOTA-sFv A33的PET研究。 我们正在生产由2个sFv分子组成的双特异性抗原结合构建体的过程中： 一种sFv靶向A33抗原，而另一种sFv与金属缀合的DOTA螯合物反应。 具体目标2将确定该构建体的最佳给药途径和靶向， 试验设计与具体目标1相似。 Specific Aim 3将使用PET评估肿瘤靶向，以及新型人源化A33 IgG的免疫原性。 这些研究将形成研究的模板，以确定sFv A33在检测中的效用， 双特异性构建体在结肠癌的检测和治疗中的用途; 以及新型非免疫原性A33 IgG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.