Dock and Lock: Novel Protein Engineering

描述（由申请人提供）：本II期申请的目的是用于乳腺癌成像的CEA-ImmunoPET的商业开发。CEA-ImmunoPET是一种双组分产品系统，包含TF 2（通过Dock and Lock（DNL）方法制备的三价、双特异性抗CEA x抗HSG构建体）和68 Ga-IMP 288（用68 Ga放射性标记的DOTA衍生化二HSG肽）。在I期SBIR（1 R43 CA 123985 -01）中，我们在TF 2的临床开发方面取得了重大进展，用于放射免疫检测和用111 In或124 I放射性标记的IMP 288治疗CEA阳性肿瘤。我们已经通过以下步骤确定了TF 2/IMP 288预靶向系统临床开发的可行性：（a）进一步优化从细胞培养物生产TF 2的工艺;（B）完成表征TF 2和IMP 288的药代动力学行为的临床前研究，以及获得将导致肿瘤的最佳预靶向的条件，（c）评估TF 2和一定程度的IMP 288的组织结合特性，和（d）启动重要的急性毒性研究，这些研究已经显示TF 2和IMP 288的安全性。在这项II期申请中，我们将完成TF 2和68 Ga-IMP 288的临床前开发，以使其有资格用于临床试验，在携带CEA表达水平不同的人肿瘤异种移植物的小鼠模型中建立最佳预靶向条件，并向FDA提交IND。我们计划在第二阶段资助期结束时开始乳腺癌成像的临床试验。公共卫生相关性：CEA-ImmunoPET的预靶向有可能成为一种方便、无创、无瘢痕、高度敏感且能够清楚区分恶性和非恶性组织的乳腺癌成像技术。

DESCRIPTION (provided by applicant): The objective of this Phase II application is the commercial development of CEA-ImmunoPET for breast cancer imaging. CEA-ImmunoPET is a two-component product system comprising TF2, a trivalent, bispecific, anti-CEA x anti-HSG constructs made by the Dock and Lock (DNL) method, and 68Ga-IMP288, a DOTA- derivatized di-HSG peptide radiolabeled with 68Ga. In the Phase I SBIR (1 R43 CA123985-01), we have achieved significant advancement towards clinical development of TF2 for radioimmunodetection and therapy of CEA-positive tumors with IMP288 radiolabeled with 111In or 124I. We have established the feasibility of clinical development of the TF2/IMP288 pretargeting system by (a) further optimizing the process of producing TF2 from cell cultures; (b) completing preclinical studies that have characterized the pharmacokinetic behavior of TF2 and IMP288 as well as obtaining the conditions that will lead to optimal pretargeting of tumors, (c) evaluating the tissue binding properties of TF2 and to some degree IMP288, and (d) initiating important acute toxicity studies that have shown the safety of both TF2 and IMP288. In this Phase II application, we will complete the preclinical development of TF2 and 68Ga-IMP288 to qualify its use for clinical trials, establish optimal pretargeting conditions in mouse models bearing human tumor xenografts that differ in the expression levels of CEA, and to submit an IND to the FDA. We plan to be in position to begin clinical trials for breast cancer imaging at the end of the Phase II funding period. PUBLIC HEALTH RELEVANCE: Pretargeting with CEA-ImmunoPET has the potential to become a breast cancer imaging technique that is convenient, non-invasive, non-scarring, highly sensitive and yet capable of clearly differentiating between malignant and non-malignant tissues.