Ben-Ami Eytan, Perret Raul, Huang Ying, Courgeon Félicie, Gokhale Prafulla C, Laroche-Clary Audrey, Eschle Benjamin K, Velasco Valérie, Le Loarer François, Algeo Marie-Paule, Purcell James, Demetri George D, Italiano Antoine
Sarcoma Division, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Pathology, Institut Bergonié, 33000 Bordeaux, France.
Cancers (Basel). 2020 Mar 23;12(3):757. doi: 10.3390/cancers12030757.
LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS).
We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS.
In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models.
We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.
LRRC15是富含亮氨酸重复序列（LRR）超家族的成员，存在于肿瘤相关成纤维细胞（CAF）和基质细胞上。LRRC15的表达受促炎细胞因子TGFβ上调。ABBV-085是一种含单甲基奥瑞他汀E（MMAE）的抗体药物偶联物（ADC），设计用于靶向LRRC15，并且在多种肿瘤模型中已显示出显著的抗肿瘤活性。这是首次对软组织肉瘤（STS）中LRRC15表达和ABBV-085活性进行的重点研究。
我们通过免疫组织化学分析了711例STS病例的LRRC15表达谱，涵盖了广泛的STS组织学类型和亚分类。使用LRRC15阳性和LRRC15阴性的STS患者来源异种移植（PDX）模型进行体内实验。
与上皮性肿瘤中观察到的模式不同，LRRC15不仅在基质细胞中表达，而且在多个STS亚组的癌细胞中也有表达，不同组织学亚型之间存在显著差异。LRRC15的过表达与分级呈正相关，并且与不良预后独立相关。ABBV-085对LRRC15阳性的STS患者来源异种移植（PDX）模型具有强大的临床前疗效。
我们提供了首个临床前证据，即使用抗体药物偶联物靶向LRRC15在LRRC15阳性的STS中是一种有前景的策略。ABBV-085正在STS和其他恶性肿瘤的一项正在进行的临床试验中进行评估。
