Abstract
Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression.
Highlights
The advancement of protein engineering has opened opportunities to generate specific functions of proteins, including bispecific molecules [1, 2]
The anti-Muc1 VHH and anti-CD16-VHH were linked by two amino acids, Glycine-Serine (Fig 1B), as the short linker does not affect single domain antibody functions
Immunotherapy has been proving as a promising cancer therapy with superior efficacy and less toxicity than many other current cancer therapies [31]
Summary
The advancement of protein engineering has opened opportunities to generate specific functions of proteins, including bispecific molecules [1, 2]. Bispecific antibodies combine specificities of two antibodies and simultaneously target two different antigens or epitopes. With the functions conferred by two different antibodies, bispecific antibodies can interfere with a variety of surface receptors or ligands, and are actively studied for many diseases, especially in cancer therapy by recruiting immune cells to directly target and kill tumor cells [3,4,5,6]. Muc is one of the most studied tumor antigens [7]. Muc belongs to the membranebound class of Mucins, which are type I membrane proteins with single transmembrane domains and different lengths of cytoplasmic tail at the C-terminus [8].
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