Anti-MICA and MICB Antibody Development

Major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) and sequence B (MICB) are expressed by many human cancers as a result of cellular stress. Creative Biolabs now provides customized antibody development services against MICA/MICB by advanced technology platform to help your projects. With extensive experience in antibody production and bio-conjugation, our professional scientists are committed to providing high-quality antibody to promote the development of innovative cancer treatments.

MICA and MICB Ectodomain Shedding

MICA and MICB are natural killer group 2D (NKG2D) ligands. They are expressed by many human cancers as a consequence of genomic damage, enabling elimination of cancer cells by cytotoxic lymphocytes expressing the NKG2D receptor. However, tumors have evolved mechanisms to escape natural killer (NK) cells surveillance by proteolytic shedding of cell surface-bound MICA/B molecules through the coordinated action of a disulfide isomerase (ERp5) and several proteases belonging to the MMP (matrix metalloproteinase) families and ADAM (a disintegrin and metalloproteinase). In detail, ADAM 10 and 17 are largely responsible for the generation of soluble MICA/B. The membrane-proximal MICA/B α3 domain is the site of proteolytic shedding, whereas the membrane-distal α1 and α2 domains bind to the NKG2D receptor.

Fig.1 Illustration of MICA protein bound to a NKG2D homodimer. (de Andrade, 2018)

Antibody Strategies against MICA and MICB

It is impossible to specifically block MICA/B shedding in vivo with small-molecule inhibitors because different proteases with broad substrate specificities contribute to this process. Antibodies can not only be used to strongly inhibit MICA/B shedding by binding to key epitopes on the α3 domain which is required for shedding without affecting the interaction between NKG2D with α1 and α2 domains, but also can be conjugated with a drug to kill tumor cells. Studies have reported that these monoclonal antibodies (mAbs) inhibit tumor growth in multiple fully immunocompetent mouse models and reduce human melanoma metastases in a humanized mouse model.

Fig.2 Schematic representation illustrating proposed therapeutic mechanism. (de Andrade, 2018)

Besides, shedding-derived soluble MICA/B (sMIC) enables tumor immune escape through several immune suppressive mechanisms, such as disturbing NK cell homeostatic maintenance, facilitating the expansion of arginase I⁺ myeloid suppressor cells, and impairing NKG2D expression on NK cells and effector T cells. sMIC neutralization can decrease lung micrometastases of sMIC⁺ tumors and restore NK cell populations and proliferation. sMIC has also been considered as an effective cancer therapeutic target. For example, the combined therapy of antibody neutralizing sMIC and immunostimulatory IL-15 superagonist complex improved the survival of animals bearing sMIC⁺ tumors in comparison to monotherapy.

Creative Biolabs is equipped with state-of-the-art research and manufacturing facilities and dedicated to helping our clients design and prepare highly customized linker and drug-linker complexes through our featured services. With the novel technique platform and professional experiment services, Creative Biolabs gets ready to provide you with the best antibody services for MICA/MICB. Please feel free to contact us for more details.

Reference

1. de Andrade, L. F.; et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science. 2018, 359 (6383), 1537-1542.

For Research Use Only. NOT FOR CLINICAL USE.