High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies

Lombana, T. Noelle; Matsumoto, Marissa L.; Bevers, Jack; Berkley, Amy M.; Toy, Evangeline; Cook, Ryan; Gan, Yutian; Du, Changchun; Liu, Peter; Schnier, Paul D.; Sandoval, Wendy; Ye, Zhengmao; Schartner, Jill; Kim, Jeong; Spiess, Christoph

doi:10.1080/19420862.2018.1532767

Cited by 13 publications

(9 citation statements)

References 47 publications

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“…Our crystal structure revealed that the epitope recognized by 1G4 (residues Asp95-Asn103) immediately follows the GPI-anchoring sequence, suggesting that it is located proximal to the cell membrane. We also used a high-resolution, high-throughput glycosylation-engineered epitope mapping (GEM) method ( 27 ) to map the location of epitopes bound by mAbs from different bins. GEM results showed that the epitopes bound by 1G4 and 6E10 were the most membrane-proximal, meanwhile, the mAbs in the other bins bound to more membrane-distal epitopes (Supplementary Table S2).…”

Section: Resultsmentioning

confidence: 99%

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Wang¹,

Sun

Clark³

et al. 2022

Molecular Cancer Therapeutics

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New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer (CRC). Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch repair-deficient or microsatellite instability-high (MSI-H) metastatic CRC (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) CRC have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this report, we describe the discovery of a novel T cell-dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D for the treatment of CRC. Expression analyses reveal limited expression of LY6G6D in normal human tissues and non-CRC tumor types; meanwhile, significant LY6G6D upregulation in CRC is observed with high prevalence in MSS and MSI-L CRC subsets. The optimized anti-LY6G6D/CD3 TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent anti-tumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB-mediated T-cell activation and cytotoxicity are conditional and target-dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates anti-tumor efficacy as a single agent against established CRC tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of anti-LY6G6D/CD3 TDB as an effective treatment option for patients with CRC.

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Section: Resultsmentioning

confidence: 99%

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Wang¹,

Sun

Clark³

et al. 2022

Molecular Cancer Therapeutics

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“…Current strategies comprise the inhibition of enzymes responsible for shedding as well as blocking the cleavage sites with therapeutic antibodies. Most likely, the efficacy of some of these new drugs will be limited to certain MICA/B alleles which increases the need for reliable genotyping (18,45).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies

et al. 2020

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MICA and MICB are ligands of the NKG2D receptor and thereby influence NK and T cell activity. MICA/B gene polymorphisms, expression levels and the amount of soluble MICA/B in the serum have been linked to autoimmune diseases, infections, and cancer. In hematopoietic stem cell transplantation, MICA matching between donor and patient has been correlated with reduced acute and chronic graft-vs.-host disease and improved survival. Hence, we developed an extremely cost-efficient high-throughput workflow for genotyping MICA/B for newly registered potential stem cell donors. Since mid-2017, we have genotyped over two million samples using NGS amplicon sequencing for MICA/B exons 2-5. In donors of German origin, MICA * 008 is the most common MICA allele with a frequency of 42.3%. It is followed by MICA * 002 (11.7%) and MICA * 009 (8.8%). The three most common MICB alleles are MICB * 005 (43.9%), MICB * 004 (21.7%), and MICB * 002 (18.9%). In general, MICB is less diverse than MICA and only 6 alleles, instead of 15, account for a cumulative allele frequency of 99.5%. In 0.5% of the samples we observed at least one allele of MICA or MICB which has so far not been reported to the IPD/IMGT-HLA database. By providing MICA/B typed voluntary donors, clinicians become empowered to include MICA/B into their donor selection process to further improve unrelated hematopoietic stem cell transplantation.

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“…В то же время следует отметить, что изменения в экспрессии белков MICA/B не являются специфической чертой канцерогенеза и могут быть вызваны рядом других факторов (вирусные заболевания, бактериальные инфекции, хроническое воспаление и т.д. [54].…”

Section: Mica/b как прогностические маркеры при онкологических заболе...unclassified

Stress-induced MICA and MICB molecules in oncology

2022

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MICA and MICB molecules, MHC class I chain-related proteins, are expressed on the membranes of damaged, transformed or infected cells. These glycoproteins bind to the NKG2D receptor of NK cells, resulting in their activation and cytotoxic response against MICA- and/or MICB-expressing cells. Expression of NKG2D receptor ligands allows the elimination of tumor and damaged cells. Soluble forms of MICA/B proteins are produced as a result of protein cleavage. Binding of soluble ligands to NKG2D receptors causes their internalization and degradation, leading to a decrease in NK cell activity. Malignant growth of gastrointestinal tissues, pancreas, liver, kidney, lung, skin, and blood cancers is accompanied by increased concentration of soluble MICA/B in blood plasma of the patients. High concentrations of these proteins are associated with lower overall and recurrence-free survival in the patients. Soluble MICA/B contribute to immunosuppressive tumor microenvironment, and increase in their plasma contents is considered an index of tumor escape from the immune surveillance. The role of MICA/B protein changes during carcinogenesis is also under studies. At the early stage of tumor formation, these proteins contribute to activation of NK cells and elimination of transformed cells, whereas, at the later stage of this process, the increased production of its soluble forms leads to a decrease in anti-tumor activity of NK cells. Standard cancer treatment, such as chemotherapy, is accompanied by increased density of these molecules on the tumor cells. In addition, preclinical studies show that inhibition of MICA/B shedding with antibodies or their derivatives may also promote the anti-tumor activity of NK cells. This review summarizes basic information on the biology of MICA/B molecules, their expression by normal and transformed cells, elucidates the role of these molecules in anti-tumor immune surveillance, and provides information on the potential use of MICA/B in diagnosis and therapy of malignant diseases.

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High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies

Cited by 13 publications

References 47 publications

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies

Stress-induced MICA and MICB molecules in oncology

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