Fluorescently labeled chimeric anti‐CEA antibody improves detection and resection of human colon cancer in a patient‐derived orthotopic xenograft (PDOX) nude mouse model

Abstract

Background and Objectives The aim of this study was to evaluate a new fluorescently labeled chimeric anti-CEA antibody for improved detection and resection of colon cancer. Methods Frozen tumor and normal human tissue samples were stained with chimeric and mouse antibody-fluorophore conjugates for comparison. Mice with patient-derived orthotopic xenografts (PDOX) of colon cancer underwent fluorescence-guided surgery (FGS) or bright-light surgery (BLS) 24 hours after tail vein injection of chimeric anti-CEA antibody. Resection completeness was assessed using postoperative images. Mice were followed for 6 months for recurrence. Results The fluorophore conjugation efficiency (dye:mole ratio) improved from 3–4 to >5.5 with the chimeric CEA antibody compared to mouse anti-CEA antibody. CEA-expressing tumors labeled with chimeric CEA antibody provided a brighter fluorescence signal on frozen human tumor tissues (p=0.046) and demonstrated consistently lower fluorescence signals in normal human tissues compared to mouse antibody. Chimeric CEA antibody accurately labeled PDOX colon cancer in nude mice, enabling improved detection of tumor margins for more effective FGS. The R0 resection rate increased from 86% to 96% with FGS compared to BLS. Conclusion Improved conjugating efficiency and labeling with chimeric fluorophore-conjugated antibody resulted in better detection and resection of human colon cancer in an orthotopic mouse model.

Specific tumor labeling enhanced by polyethylene glycol linkage of near infrared dyes conjugated to a chimeric anti-carcinoembryonic antigen antibody in a nude mouse model of human pancreatic cancer

“…The cumulative effects of PEGylation were to increase dye-conjugated anti-CEA antibody half-life, favorably alter the biodistribution, and significantly increase tumor to background contrast. PEGylated dyes conjugated to tumor-specific antibodies should have an important impact in the development of fluorescence guided surgery of cancer, 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] as these dyes offer the possibility of high fidelity-targeted tumor and metastases labeling.…”

Intra-arterial administration of tumor-targetingSalmonella typhimuriumA1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

“…Toward the goal of precision oncology, our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI), including pancreatic, [1][2][3][4] breast, 5 ovarian, 6 lung, 7 cervical, 8 colon, [9][10][11] and stomach cancer, 12 sarcoma, [13][14][15][16][17] and melanoma. [18][19][20] In a previous study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared with cisplatinum (CDDP) on a lung-metastatic osteosarcoma PDOX mouse model.…”

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

“…PDOX models, which were implanted using intact tumor tissue with the technique of surgical orthotopic implantation (SOI) (25,27), were established from patients with colonic (28)(29)(30), pancreatic (21, 31-41), breast (42), ovarian (43), lung (44), and stomach cancer (45), and mesothelioma (46) in the early 1990s, resulting in primary and metastatic tumor growth very similar to that in the patient.…”