Targeting Human C-Type Lectin-like Molecule-1 (CLL1) with a Bispecific Antibody for Immunotherapy of Acute Myeloid Leukemia†
Dr. Hua Lu
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorDr. Quan Zhou
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorVishal Deshmukh
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorDr. Hardeep Phull
Scripps Translational Science Institute, 3344 N Torrey Pines Ct, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Jennifer Ma
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Virginie Tardif
Department of Immunology and Microbial Science, The Scripps Research Institute (USA)
Search for more papers by this authorDr. Rahul R. Naik
Division of Hematology and Oncology, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Claire Bouvard
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Yong Zhang
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Seihyun Choi
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Brian R. Lawson
Department of Immunology and Microbial Science, The Scripps Research Institute (USA)
Search for more papers by this authorDr. Shoutian Zhu
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Dr. Chan Hyuk Kim
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Chan Hyuk Kim, California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Peter G. Schultz, Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Dr. Peter G. Schultz
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Chan Hyuk Kim, California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Peter G. Schultz, Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Hua Lu
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorDr. Quan Zhou
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorVishal Deshmukh
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
These authors contributed equally to this work.
Search for more papers by this authorDr. Hardeep Phull
Scripps Translational Science Institute, 3344 N Torrey Pines Ct, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Jennifer Ma
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Virginie Tardif
Department of Immunology and Microbial Science, The Scripps Research Institute (USA)
Search for more papers by this authorDr. Rahul R. Naik
Division of Hematology and Oncology, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Claire Bouvard
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Yong Zhang
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Seihyun Choi
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorDr. Brian R. Lawson
Department of Immunology and Microbial Science, The Scripps Research Institute (USA)
Search for more papers by this authorDr. Shoutian Zhu
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Dr. Chan Hyuk Kim
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Chan Hyuk Kim, California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Peter G. Schultz, Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorCorresponding Author
Dr. Peter G. Schultz
Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Chan Hyuk Kim, California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Peter G. Schultz, Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA)
Search for more papers by this authorThis work is supported by NIH grant R01 GM097206. H.L. is The Jake Wetchler Foundation Fellow for Pediatric Innovation of the Damon Runyon Cancer Research Foundation DRG-2099-11.
Graphical Abstract
A bispecific antibody, αCLL1-αCD3, was synthesized using a genetically encoded unnatural amino acid, and shown to recruit cytotoxic T cells to CLL1-positive cells. The reported results validate the clinical potential of CLL1 as an AML-specific antigen for the generation of bispecific antibodies for the treatment of acute myeloid leukemia (AML).
Abstract
Acute myeloid leukemia (AML), which is the most common acute adult leukemia and the second most common pediatric leukemia, still has a poor prognosis. Human C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90 % of AML patient myeloid blasts and in leukemic stem cells. Here, we describe the synthesis of a novel bispecific antibody, αCLL1-αCD3, using the genetically encoded unnatural amino acid, p-acetylphenylalanine. The resulting αCLL1-αCD3 recruits cytotoxic T cells to CLL1 positive cells, and demonstrates potent and selective cytotoxicity against several human AML cell lines and primary AML patient derived cells in vitro. Moreover, αCLL1-αCD3 treatment completely eliminates established tumors in an U937 AML cell line xenograft model. These results validate the clinical potential of CLL1 as an AML-specific antigen for the generation of a novel immunotherapeutic for AML.
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