Selective Photokilling of Colorectal Tumors by Near-Infrared Photoimmunotherapy with a GPA33-Targeted Single-Chain Antibody Variable Fragment Conjugate.

Abstract

Antibody-based near-infrared photoimmunotherapy (NIR-PIT) is an attractive strategy for cancer treatment. Tumor cells can be selectively and efficiently killed by the targeted delivery of an antibody-photoabsorber complex followed by exposure to NIR light. Glycoprotein A33 antigen (GPA33) is highly expressed in most human colorectal cancers (CRCs) and is an ideal diagnostic and therapeutic target. We previously produced a single-chain fragment of a variable antibody against GPA33 (A33scFv antibody). Here, we investigate the efficacy of NIR-PIT by combining A33scFv with the NIR photoabsorber IR700 (A33scFv-IR700). In vitro, recombinant A33scFv displayed specific binding and delivery of an NIR dye to GPA33-positive tumor cells. Furthermore, A33scFv-IR700-mediated NIR-PIT was successful in rapidly and specifically killing GPA33-positive colorectal tumor cells. NIR-PIT treatment induced the release of lactate dehydrogenase from tumor cells, followed by cell necrosis, rather than apoptosis, through the promotion of reactive oxygen species accumulation in tumor cells. In mice bearing LS174T tumor grafts, A33scFv selectively accumulated in GPA33-positive tumors. Following only a single injection of the conjugate and subsequent illumination, A33scFv-IR700-mediated NIR-PIT induced a significant increase in therapeutic response in LS174T-tumor mice compared with that in the non-NIR-PIT groups (p < 0.001). Because the GPA33 antigen is specifically expressed in CRC tumors, A33scFv-IR700 might be a promising antibody fragment-photoabsorber conjugate for NIR-PIT of CRC.

• Authors: Danfeng Wei, Ze Tao, Qiuxiao Shi, Lijun Wang, Lei Liu, Tianshan She, Qin Yi, Xiang Wen, Lian Liu, Shengfu Li, Hao Yang, Xian Jiang
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 17 Issue 7 Pg. 2508-2517 (07 06 2020) ISSN: 1543-8392 [Electronic] United States
• PMID: 32396000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GPA33 protein, human
• Immunoconjugates
• Membrane Glycoproteins
• Photosensitizing Agents
• Reactive Oxygen Species
• Single-Chain Antibodies
• L-Lactate Dehydrogenase

Topics

• Animals
• Cell Death (drug effects, immunology)
• Colorectal Neoplasms (drug therapy, immunology, radiotherapy)
• HT29 Cells
• Humans
• Immunoconjugates (therapeutic use)
• Immunotherapy (methods)
• L-Lactate Dehydrogenase (metabolism)
• Mass Spectrometry
• Membrane Glycoproteins (immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Necrosis (metabolism)
• Photosensitizing Agents (therapeutic use)
• Phototherapy (methods)
• Reactive Oxygen Species (metabolism)
• Single-Chain Antibodies (immunology, radiation effects, toxicity)
• Xenograft Model Antitumor Assays