6brb

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Novel non-antibody protein scaffold targeting CD40L

Structural highlights

6brb is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.82Å
Ligands:BMA, NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CD40L_HUMAN Defects in CD40LG are the cause of X-linked immunodeficiency with hyper-IgM type 1 (HIGM1) [MIM:308230; also known as X-linked hyper IgM syndrome (XHIM). HIGM1 is an immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Function

CD40L_HUMAN Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL-4. Involved in immunoglobulin class switching.[11] Release of soluble CD40L from platelets is partially regulated by GP IIb/IIIa, actin polymerization, and an matrix metalloproteinases (MMP) inhibitor-sensitive pathway.[12]

Publication Abstract from PubMed

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67(+) dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.,Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, Oganesyan V, Gunsior M, Thisted T, Yan L, Li J, Xiong X, Eck SC, de Los Reyes M, Yusuf I, Streicher K, Muller-Ladner U, Howe D, Ettinger R, Herbst R, Drappa J Sci Transl Med. 2019 Apr 24;11(489). pii: 11/489/eaar6584. doi:, 10.1126/scitranslmed.aar6584. PMID:31019027[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
29 reviews cite this structure
Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells.
Jang et al. (2022)
28 more
17 other articles
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See Also

References

  1. ↑ Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, et al.. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291-300. PMID:7678782
  2. ↑ Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539-41. PMID:7679206 doi:http://dx.doi.org/10.1038/361539a0
  3. ↑ DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541-3. PMID:8094231 doi:http://dx.doi.org/10.1038/361541a0
  4. ↑ Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, et al.. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990-3. PMID:7679801
  5. ↑ Macchi P, Villa A, Strina D, Sacco MG, Morali F, Brugnoni D, Giliani S, Mantuano E, Fasth A, Andersson B, et al.. Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry. Am J Hum Genet. 1995 Apr;56(4):898-906. PMID:7717401
  6. ↑ Saiki O, Tanaka T, Wada Y, Uda H, Inoue A, Katada Y, Izeki M, Iwata M, Nunoi H, Matsuda I, et al.. Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM. J Clin Invest. 1995 Feb;95(2):510-4. PMID:7532185 doi:http://dx.doi.org/10.1172/JCI117692
  7. ↑ Katz F, Hinshelwood S, Rutland P, Jones A, Kinnon C, Morgan G. Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome. Hum Mutat. 1996;8(3):223-8. PMID:8889581 doi:<223::AID-HUMU5>3.0.CO;2-A 10.1002/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A
  8. ↑ Lin Q, Rohrer J, Allen RC, Larche M, Greene JM, Shigeoka AO, Gatti RA, Derauf DC, Belmont JW, Conley ME. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. 1996 Jan 1;97(1):196-201. PMID:8550833 doi:http://dx.doi.org/10.1172/JCI118389
  9. ↑ Nonoyama S, Shimadzu M, Toru H, Seyama K, Nunoi H, Neubauer M, Yata J, Och HD. Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. Hum Genet. 1997 May;99(5):624-7. PMID:9150729
  10. ↑ Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood. 1998 Oct 1;92(7):2421-34. PMID:9746782
  11. ↑ Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055
  12. ↑ Furman MI, Krueger LA, Linden MD, Barnard MR, Frelinger AL 3rd, Michelson AD. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization. J Am Coll Cardiol. 2004 Jun 16;43(12):2319-25. PMID:15193700 doi:10.1016/j.jacc.2003.12.055
  13. ↑ Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, Oganesyan V, Gunsior M, Thisted T, Yan L, Li J, Xiong X, Eck SC, de Los Reyes M, Yusuf I, Streicher K, Muller-Ladner U, Howe D, Ettinger R, Herbst R, Drappa J. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl Med. 2019 Apr 24;11(489). pii: 11/489/eaar6584. doi:, 10.1126/scitranslmed.aar6584. PMID:31019027 doi:http://dx.doi.org/10.1126/scitranslmed.aar6584

Contents


PDB ID 6brb

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