title: TCR-like antibody drug conjugates mediate killing of tumor cells with low peptide/HLA targets.
abstract: The currently marketed antibody-drug conjugates (ADC) destabilize microtubule assembly in cancer cells and initiate apoptosis in patients. However, few tumor antigens (TA) are expressed at high densities on cancer lesions, potentially minimizing the therapeutic index of current ADC regimens. The peptide/human leukocyte antigen (HLA) complex can be specifically targeted by therapeutic antibodies (designated T cell receptor [TCR]-like antibodies) and adequately distinguish malignant cells, but has not been the focus of ADC development. We analyzed the killing potential of TCR-like ADCs when cross-linked to the DNA alkylating compound duocarmycin. Our data comprise proof-of-principle results that TCR-like ADCs mediate potent tumor cytotoxicity, particularly under common scenarios of low TA/HLA density, and support their continued development alongside agents that disrupt DNA replication. Additionally, TCR-like antibody ligand binding appears to play an important role in ADC functionality and should be addressed during therapy development to avoid binding patterns that negate ADC killing efficacy.
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Devin B
authors.initials: DB
authors.lastname: Lowe
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Camille K
authors.initials: CK
authors.lastname: Bivens
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Alexis S
authors.initials: AS
authors.lastname: Mobley
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Herrera
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: McCormick
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Timea
authors.initials: T
authors.lastname: Wichner
authors.affiliation: b Department of Biology , College of Science, University of Texas at Arlington , Arlington , TX , USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Sabnani
authors.affiliation: a Department of Immunotherapeutics and Biotechnology , School of Pharmacy, Texas Tech University Health Sciences Center , Abilene , TX , USA.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Wood
authors.affiliation: b Department of Biology , College of Science, University of Texas at Arlington , Arlington , TX , USA.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Weidanz
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D000080890:Duocarmycins; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology*; D011760:Pyrrolidinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell
chemical_list: D000912:Antibodies, Neoplasm; D000080890:Duocarmycins; D006680:HLA Antigens; D007211:Indoles; D010455:Peptides; D011760:Pyrrolidinones; D011948:Receptors, Antigen, T-Cell; C058289:duocarmycin A
keywords: Antibody drug conjugate; TCR-like antibody; cancer; duocarmycin; human leukocyte antigen; immunotherapy