Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Cancer Res. 2023 Jun 15;83(12):2052-2065. doi: 10.1158/0008-5472.CAN-22-1532.
Metastases are hard to detect and treat, and they cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix (ECM) forms a major component of the tumor microenvironment in both primary and metastatic tumors, and certain ECM proteins can be selectively and abundantly expressed in tumors. Nanobodies against ECM proteins that show selective abundance in metastases have the potential to be used as vehicles for delivery of imaging and therapeutic cargoes. Here, we describe a strategy to develop phage-display libraries of nanobodies against ECM proteins expressed in human metastases, using entire ECM-enriched preparations from triple-negative breast cancer (TNBC) and colorectal cancer metastases to different organs as immunogens. In parallel, LC-MS/MS-based proteomics were used to define a metastasis-associated ECM signature shared by metastases from TNBC and colorectal cancer, and this conserved set of ECM proteins was selectively elevated in other tumors. As proof of concept, selective and high-affinity nanobodies were isolated against an example protein from this signature, tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastasis. TNC was abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Immuno-PET/CT showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic nanobodies against tumors and metastases are promising cancer-agnostic tools for delivery of therapeutics to tumor and metastatic ECM.
Nanobodies specific for extracellular matrix markers commonly expressed in primary tumors and metastases are promising agents for noninvasive detection of tumors and metastases and potential tools for targeted therapy.
转移很难被发现和治疗，它们导致了大多数癌症相关的死亡。针对转移的治疗方法相对较少，这是一个未满足的主要临床需求。细胞外基质 (ECM) 是原发性和转移性肿瘤微环境的主要组成部分，某些 ECM 蛋白可以在肿瘤中选择性地大量表达。针对 ECM 蛋白的纳米抗体，如果在转移中选择性地大量表达，有可能被用作递呈成像和治疗药物的载体。在这里，我们描述了一种使用来自三阴性乳腺癌 (TNBC) 和结直肠癌转移到不同器官的整个 ECM 富集制剂作为免疫原，开发针对 ECM 蛋白的噬菌体展示文库的策略。同时，我们使用基于 LC-MS/MS 的蛋白质组学来定义一个由 TNBC 和结直肠癌转移共享的与 ECM 相关的转移标志，这个保守的 ECM 蛋白集合在其他肿瘤中选择性地升高。作为概念验证，我们从这个标志中选择了一个例子蛋白——层粘连蛋白 C (TNC)，针对其分离出了具有选择性和高亲和力的纳米抗体，TNC 在许多肿瘤类型中大量表达，并且在转移中发挥作用。TNC 在患者转移中大量表达，并广泛表达于来自几种原发性肿瘤类型的多种转移性部位。免疫 PET/CT 显示，抗 TNC 纳米抗体与 TNBC 肿瘤和转移具有极好的特异性结合。我们提出，针对肿瘤和转移的通用纳米抗体是一种有前途的、针对肿瘤和转移 ECM 的无偏治疗药物递呈工具。
针对在原发性肿瘤和转移中普遍表达的细胞外基质标志物的纳米抗体是一种有前途的非侵入性检测肿瘤和转移的试剂，也是一种潜在的靶向治疗工具。
