Samkoe Kimberley S, Sardar Hira Shahzad, Gunn Jason R, Elliott Jonathan Thomas, Mansur Sally, Feldwisch Joachim, Pogue Brian W, Linos Konstantinos, Paulsen Keith D, Henderson Eric R
Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
Mol Cancer Ther. 2025 May 2;24(5):784-795. doi: 10.1158/1535-7163.MCT-24-0378.
ABY-029, an anti-EGFR Affibody molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma. The FDA Exploratory Investigational New Drug status was obtained for the phase 0 clinical trial in which study objectives were to determine whether a biological variance ratio (BVR) of 10 was achievable, whether fluorescence intensity correlated with EGFR expression, and whether doses were well tolerated. Patients (N = 12) with soft-tissue sarcoma were recruited based on positive EGFR IHC staining of diagnostic biopsies. ABY-029 was administered at a microdose (30 nmol, n = 3), medium dose (90 nmol, n = 3), or high dose (171 nmol, n = 6) 1 to 3 hours prior to surgery. Following tumor resection, ex vivo tissue was imaged to determine the mean fluorescence intensity, BVR, and other contrast measures. EGFR expression was correlated with IHC. For micro, medium, and high doses, mean BVR (SD) values in cross-sectional slices were 4 (4), 10 (6), and 7 (8) for the whole tumor region and 6 (5), 13 (11), and 8 (6) for pathology-confirmed regions of interest, respectively. Strong linear correlations were found between all ABY-029 contrast metrics and total EGFR (r≥ 0.86; P < 0.029) in cross-sectional tissue slices and between mean fluorescence intensity and EGFR percent area (r = 0.63; P < 0.0001) in excised region-of-interest tissue sections. No ABY-029-related adverse events were observed. When administered above the microdose, ABY-029 demonstrated a high correlation with EGFR expression and contrast values that were encouraging for translation to clinical practice. Contrast values were similar to those observed with antibody agents but with a substantially reduced imaging-to-resection time and no drug-related adverse events.
ABY-029是一种与IRDye 800CW偶联的抗表皮生长因子受体（EGFR）亲和体分子，最近在软组织肉瘤患者中进行了首次人体试验。该药物在0期临床试验中获得了美国食品药品监督管理局（FDA）探索性研究新药的地位，该试验的研究目的是确定是否能够实现10的生物学差异率（BVR），荧光强度是否与EGFR表达相关，以及剂量是否具有良好的耐受性。根据诊断性活检的EGFR免疫组化染色阳性，招募了12例软组织肉瘤患者。在手术前1至3小时，分别以微剂量（30 nmol，n = 3）、中剂量（90 nmol，n = 3）或高剂量（171 nmol，n = 6）给予ABY-029。肿瘤切除后，对离体组织进行成像，以确定平均荧光强度、BVR和其他对比指标。EGFR表达与免疫组化结果相关。对于微剂量、中剂量和高剂量，整个肿瘤区域横截面切片的平均BVR（标准差）值分别为4（4）、10（6）和7（8），病理确认的感兴趣区域分别为6（5）、13（11）和8（6）。在横截面组织切片中，所有ABY-029对比指标与总EGFR之间均存在强线性相关性（r≥0.86；P < 0.029），在切除的感兴趣区域组织切片中，平均荧光强度与EGFR面积百分比之间也存在强线性相关性（r = 0.63；P < 0.0001）。未观察到与ABY-029相关的不良事件。当给药剂量高于微剂量时，ABY-029与EGFR表达和对比值高度相关，这为其转化为临床应用带来了希望。对比值与抗体药物观察到的结果相似，但成像至切除时间大幅缩短，且无药物相关不良事件。
