CD276 explained

Cluster of Differentiation 276 (CD276) or B7 Homolog 3 (B7-H3) is a human protein encoded by the gene.^[1]

Structure

B7-H3 is a 316 amino acid-long type I transmembrane protein, existing in two isoforms determined by its extracellular domain. In mice, the extracellular domain consists of a single pair of immunoglobulin variable (IgV)-like and immunoglobulin constant (IgC)-like domains, whereas in humans it consists of one pair (2Ig-B7-H3) or two identical pairs (4Ig-B7-H3) due to exon duplication. B7-H3 mRNA is expressed in most normal tissues. In contrast, B7-H3 protein has a very limited expression on normal tissues because of its post-transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types (60% of all cancers). ^[2] The 4Ig-B7-H3 isoform is predominant in cancer.^[3]

Function

In non-malignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T cell activation and proliferation.

In malignant tissues, B7-H3 is an immune checkpoint molecule that inhibits tumor antigen-specific immune responses. B7-H3 also possesses non-immunological pro-tumorigenic functions such as promoting migration, invasion, angiogenesis, chemoresistance, epithelial-to-mesenchymal transition, and affecting tumor cell metabolism.

As a possible drug target

Due to its selective expression on solid tumors, B7-H3 has been the target of several anticancer agents such as enoblituzumab (MGA271),^[4] omburtamab, MGD009, MGC018, DS-7300a, and CAR T cells. Nanobodies targeting the IgV and IgC domains of B7-H3 have been developed in the laboratory of Mitchell Ho at the NCI, NIH (Bethesda, US). The nanobody-based CAR T cells are active in preclinical models of pancreatic cancer and neuroblastoma and show efficacy against large tumors in mice.

See also

• Cluster of differentiation

Further reading

• Kontos F, Michelakos T, Kurokawa T, Sadagopan A, Schwab JH, Ferrone CR, Ferrone S . B7-H3: An Attractive Target for Antibody-based Immunotherapy . Clinical Cancer Research . 27 . 5 . 1227–1235 . March 2021 . 33051306 . 7925343 . 10.1158/1078-0432.CCR-20-2584 .
• Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, Chen L . 6 . B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production . Nature Immunology . 2 . 3 . 269–274 . March 2001 . 11224528 . 10.1038/85339 . 43480199 .
• Sun M, Richards S, Prasad DV, Mai XM, Rudensky A, Dong C . Characterization of mouse and human B7-H3 genes . Journal of Immunology . 168 . 12 . 6294–6297 . June 2002 . 12055244 . 10.4049/jimmunol.168.12.6294 . free .
• Ling V, Wu PW, Spaulding V, Kieleczawa J, Luxenberg D, Carreno BM, Collins M . Duplication of primate and rodent B7-H3 immunoglobulin V- and C-like domains: divergent history of functional redundancy and exon loss . Genomics . 82 . 3 . 365–377 . September 2003 . 12906861 . 10.1016/S0888-7543(03)00126-5 .
• Steinberger P, Majdic O, Derdak SV, Pfistershammer K, Kirchberger S, Klauser C, Zlabinger G, Pickl WF, Stöckl J, Knapp W . 6 . Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains . Journal of Immunology . 172 . 4 . 2352–2359 . February 2004 . 14764704 . 10.4049/jimmunol.172.4.2352 . free .
• Zhang GB, Chen YJ, Shi Q, Ma HB, Ge Y, Wang Q, Jiang Z, Xu Y, Zhang XG . 6 . Human recombinant B7-H3 expressed in E. coli enhances T lymphocyte proliferation and IL-10 secretion in vitro . Acta Biochimica et Biophysica Sinica . 36 . 6 . 430–436 . June 2004 . 15188059 . 10.1093/abbs/36.6.430 .
• Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, Negri F, Conte R, Corrias MV, Moretta L, Moretta A, Bottino C . 6 . Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis . Proceedings of the National Academy of Sciences of the United States of America . 101 . 34 . 12640–12645 . August 2004 . 15314238 . 515110 . 10.1073/pnas.0405025101 . free . 2004PNAS..10112640C .
• Wang L, Fraser CC, Kikly K, Wells AD, Han R, Coyle AJ, Chen L, Hancock WW . 6 . B7-H3 promotes acute and chronic allograft rejection . European Journal of Immunology . 35 . 2 . 428–438 . February 2005 . 15682454 . 10.1002/eji.200425518 . 607942 .
• Kim J, Myers AC, Chen L, Pardoll DM, Truong-Tran QA, Lane AP, McDyer JF, Fortuno L, Schleimer RP . 6 . Constitutive and inducible expression of b7 family of ligands by human airway epithelial cells . American Journal of Respiratory Cell and Molecular Biology . 33 . 3 . 280–289 . September 2005 . 15961727 . 2715317 . 10.1165/rcmb.2004-0129OC .
• Petroff MG, Kharatyan E, Torry DS, Holets L . The immunomodulatory proteins B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human placenta . The American Journal of Pathology . 167 . 2 . 465–473 . August 2005 . 16049332 . 1603571 . 10.1016/S0002-9440(10)62990-2 .
• Zhang G, Dong Q, Xu Y, Yu G, Zhang X . B7-H3: another molecule marker for Mo-DCs? . Cellular & Molecular Immunology . 2 . 4 . 307–311 . August 2005 . 16274630 .
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . 6 . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–126 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Sakthivel P, Wang X, Gharizadeh B, Giscombe R, Pirskanen R, Nyren P, Lefvert AK . Single-nucleotide polymorphisms in the B7H3 gene are not associated with human autoimmune myasthenia gravis . Journal of Genetics . 85 . 3 . 217–220 . December 2006 . 17406098 . 10.1007/BF02935335 . 20818492 .

Notes and References

1. Web site: Entrez Gene: CD276 CD276 molecule.
2. Kontos F, Michelakos T, Kurokawa T, Sadagopan A, Schwab JH, Ferrone CR, Ferrone S . B7-H3: An Attractive Target for Antibody-based Immunotherapy . Clinical Cancer Research . 27 . 5 . 1227–1235 . March 2021 . 33051306 . 7925343 . 10.1158/1078-0432.CCR-20-2584 .
3. Li D, Wang R, Liang T, Ren H, Park C, Tai CH, Ni W, Zhou J, Mackay S, Edmondson E, Khan J, Croix BS, Ho M . 6 . Camel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours . Nature Communications . 14 . 1 . 5920 . September 2023 . 37739951 . 10517151 . 10.1038/s41467-023-41631-w . 2023NatCo..14.5920L .
4. Web site: Servier Pays MacroGenics $20M for Option to Anticancer Antibody - GEN. GEN. December 2011.