Dock and Lock: Novel Protein Engineering

描述(由申请人提供)：此第二阶段申请的目标是用于乳腺癌成像的CEA-免疫PET的商业开发。CEA-免疫PET是一个由TF2和68Ga-IMP288组成的双组分产物系统。TF2是一种三价、双特异性、抗CEA x抗HSG的载体，由DNL方法构建，68Ga-IMP288是一种标记有68Ga的DOTA衍生的双HSG多肽。在第一阶段的SBIR(1 R43 CA123985-01)中，我们已经在TF2的临床开发方面取得了重大进展，TF2用于放射免疫检测和用111In或124I标记的IMP288治疗CEA阳性肿瘤。我们已经确定了TF2/IMP288预靶向系统临床开发的可行性，方法是：(A)进一步优化从细胞培养生产TF2的过程；(B)完成表征TF2和IMP288药代动力学行为的临床前研究，并获得导致最佳预靶向肿瘤的条件，(C)评估TF2和IMP288的组织结合特性，以及(D)启动重要的急性毒性研究，表明TF2和IMP288都是安全的。在这个第二阶段的应用中，我们将完成TF2和68Ga-IMP288的临床前开发，以使其有资格用于临床试验，在携带不同CEA表达水平的人肿瘤异种移植瘤的小鼠模型中建立最佳的预靶向条件，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免疫PET定位有可能成为一种方便、非侵入性、无疤痕、高度敏感且能够明确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.