Strickland Laura A, Ross Jed, Williams Simon, Ross Sarajane, Romero Maria, Spencer Susan, Erickson Rich, Sutcliffe Julie, Verbeke Caroline, Polakis Paul, van Bruggen Nicholas, Koeppen Hartmut
Department of Pathology, Genentech Inc., South San Francisco, CA, USA.
J Pathol. 2009 Jul;218(3):380-90. doi: 10.1002/path.2545.
Despite the availability of new targeted therapies, ductal pancreatic adenocarcinoma continues to carry a poor prognosis. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)6 has been reported as a potential biomarker and therapy target for this malignancy. We have evaluated CEACAM6 as a potential therapy target, using an antibody-drug conjugate (ADC). Expression of CEACAM6 in pancreatic adenocarcinomas was determined using immunohistochemistry on tissue microarrays. The expression pattern in granulocytes and granulocytic precursors was measured by flow cytometry. Murine xenograft and non-human primate models served to evaluate efficacy and safety, respectively. Robust expression of CEACAM6 was found in > 90% of invasive pancreatic adenocarcinomas as well as in intraepithelial neoplastic lesions. In the granulocytic lineage, CEACAM6 was expressed at all stages of granulocytic maturation except for the early lineage-committed precursor cell. The anti-CEACAM6 ADC showed efficacy against established CEACAM6-expressing tumours. In non-human primates, antigen-dependent toxicity of the ADC consisted of dose-dependent and reversible depletion of granulocytes and their precursors. This was associated with preferential and rapid localization of the antibody in bone marrow, as determined by sequential in vivo PET imaging of the radiolabelled anti-CEACAM6. Localization of the radiolabelled tracer could be attenuated by predosing with unlabelled antibody confirming specific accumulation in this compartment. Based on the expression pattern in normal and malignant pancreatic tissues, efficacy against established tumours and limited and reversible bone marrow toxicity, we propose that CEACAM6 should be considered for an ADC-based therapy approach against pancreatic adenocarcinomas and possibly other CEACAM6-positive neoplasms.
尽管有了新的靶向疗法，但导管腺癌的预后仍然很差。癌胚抗原相关细胞粘附分子（CEACAM）6已被报道为这种恶性肿瘤的潜在生物标志物和治疗靶点。我们使用抗体药物偶联物（ADC）评估了CEACAM6作为潜在治疗靶点的情况。通过组织微阵列上的免疫组织化学确定胰腺腺癌中CEACAM6的表达。通过流式细胞术测量粒细胞和粒细胞前体中的表达模式。小鼠异种移植模型和非人类灵长类动物模型分别用于评估疗效和安全性。在超过90%的浸润性胰腺腺癌以及上皮内肿瘤性病变中发现了CEACAM6的强烈表达。在粒细胞谱系中，除了早期谱系定向前体细胞外，CEACAM6在粒细胞成熟的所有阶段均有表达。抗CEACAM6 ADC对已建立的表达CEACAM6的肿瘤显示出疗效。在非人类灵长类动物中，ADC的抗原依赖性毒性包括粒细胞及其前体的剂量依赖性和可逆性耗竭。这与抗体在骨髓中的优先和快速定位有关，这是通过对放射性标记的抗CEACAM6进行连续体内PET成像确定的。预先给予未标记的抗体可以减弱放射性标记示踪剂的定位，证实了在该区域的特异性积累。基于正常和恶性胰腺组织中的表达模式、对已建立肿瘤的疗效以及有限且可逆的骨髓毒性，我们建议应考虑将CEACAM6用于基于ADC的治疗方法来治疗胰腺腺癌以及可能的其他CEACAM6阳性肿瘤。
