CD3e

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2742

Nomenclature: CD3e

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	207	11q23.3	CD3E	CD3 epsilon subunit of T-cell receptor complex
Mouse	1	189	9 24.84 cM	Cd3e	CD3 antigen, epsilon polypeptide
Rat	-	188	8q22	Cd3e	CD3 epsilon subunit of T-cell receptor complex

Previous and Unofficial Names
Cde3 \| CD3 antigen, epsilon polypeptide \| CD3e molecule, epsilon (CD3-TCR complex) \| CD3 molecule, epsilon \| CD3 antigen \| CD3e molecule

Database Links
Alphafold	P07766 (Hs), P22646 (Mm)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL1975 (Hs)
DrugBank Target	P07766 (Hs)
Ensembl Gene	ENSG00000198851 (Hs), ENSMUSG00000032093 (Mm), ENSRNOG00000016069 (Rn)
Entrez Gene	916 (Hs), 12501 (Mm), 315609 (Rn)
Human Protein Atlas	ENSG00000198851 (Hs)
KEGG Gene	hsa:916 (Hs), mmu:12501 (Mm), rno:315609 (Rn)
OMIM	186830 (Hs)
Pharos	P07766 (Hs)
RefSeq Nucleotide	NM_000733 (Hs), NM_007648 (Mm), NM_001108140 (Rn)
RefSeq Protein	NP_000724 (Hs), NP_031674 (Mm), NP_001101610 (Rn)
UniProtKB	P07766 (Hs), P22646 (Mm)
Wikipedia	CD3E (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Antibodies

Key to terms and symbols

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Antibody		Sp.	Action	Value	Parameter	Reference
tarlatamab		Hs	Binding	8.4	pK_d	12
⤷	pK_d 8.4 (K_d 4.4x10^-9 M) [12]
ZWB67		Hs	Binding	8.0	pK_d	28
⤷	pK_d 8.0 (K_d 1x10^-8 M) [28]
PF-07062119		Hs	Binding	7.6	pK_d	18
⤷	pK_d 7.6 (K_d 2.397x10^-8 M) [18] Description: Binding affinity for human CD3ε in a SPR BIACore assay.
PF-07062119		Monkey	Binding	7.6	pK_d	18
⤷	pK_d 7.6 (K_d 2.412x10^-8 M) [18] Description: Binding affinity for cynomolgus CD3ε in a SPR BIACore assay.
blinatumomab		Hs	Binding	7.0	pK_d	10
⤷	pK_d 7.0 (K_d 1x10^-7 M) [10] Description: Binding of the single-chain Fv portion of blinatumomab to CD3.
tepoditamab		Hs	Binding	6.8	pK_d	26
⤷	pK_d 6.8 (K_d 1.77x10^-7 M) [26] Description: Binding affinity for hCD3 determined by surface plasmon resonance.
muromonab-CD3		Hs	Binding	-	-	13
⤷	[13]
catumaxomab		Hs	Binding	-	-	17
⤷	[17]
otelixizumab		Hs	Binding	-	-	3
⤷	[3]
epcoritamab		Hs	Binding	-	-	11
⤷	[11]
teplizumab		Hs	Binding	-	-	21,27
⤷	[21,27]
mosunetuzumab		Hs	Agonist	-	-	23
⤷	[23]

Antibody Comments

Visilizumab (HuM291, Nuvion) is a humanized IgG₂ anti-CD3e mAb that was engineered to prevent Fc receptor binding [24-25], a concept designed to minimise the mAb-induced cytokine release syndrome associated with exposure to conventional mAbs [7,19]. Visilizumab was developed as a potential immunosuppressive therapeutic for autoimmune diseases and as a prophylactic for transplant rejection. However this mAb failed to show significant clinical efficacy in kidney transplantation, psoriasis, GvHD and IBD, and development appears to have ceased. Visilizumab (humanized m291 IgG2M3 antibody claimed in US5834597) binds human CD3e with a K_a of 50nM [25].
Amgen have a CD3e/TNFRSF17 (or B-cell maturation antigen, BCMA) bispecific mAb called AMG420 (and previously known as BI 836909 [14]) in their immuno-oncology development pipeline as a novel last-line therapy for the treatment of relapsed/refractory multiple myeloma (see clinical trial NCT02514239 for further details).

Other Binding Ligands

Key to terms and symbols

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Ligand											Sp.	Action	Value	Parameter	Reference
AX-024											Hs	Binding	9.0	pIC₅₀	4
⤷	pIC₅₀ 9.0 (IC₅₀ 1x10^-9 M) [4] Description: Inhibition of binding between a synthetic peptide corresponding to the PRS of CD3e and an immobilized SH3.1 domain of human Nck1, by surface plasmon resonance.

Immunopharmacology Comments
CD3e is a subunit of the T cell receptor (TCR)-CD3 complex that mediates T cell receptor signal transduction in response to antigen detection. The TCR complex contains a CD3γ chain (CD3G), a CD3δ chain (CD3D), and two CD3ε chains (CD3E), plus the TCR (that can be α/β, or γ/δ type in the subsets of T cells named after the TCR they express) and the ζ-chain (zeta-chain). CD3e plays a crucial role in T cell development, highlighted by the discovery that defects in CD3e cause severe immunodeficiency [8,22]. Therapeutic anti-CD3e monoclonal antibodies (mAbs) have been developed and investigated for clinically beneficial effects in autoimmune diseases (inflammatory bowel diseases [1,16] and type 1 diabetes [15,20]) and transplantation (graft-versus-host disease [5-6,29] and renal transplantation [19]) CD3e-targeting mAbs may be useful in combination with other therapies [2,9]. Anti-CD3e antibodies that are engineered to bind additional cellular targets and which selectively target the immune destruction of cancer cells are approved for use in immuno-oncology indications (e.g. blinatumomab and catumaxomab). Muromonab-CD3 was used to prevent rejection of organ allografts, but was withdrawn from the market due to lack of demand.

Immunopharmacology Comments

CD3e is a subunit of the T cell receptor (TCR)-CD3 complex that mediates T cell receptor signal transduction in response to antigen detection. The TCR complex contains a CD3γ chain (CD3G), a CD3δ chain (CD3D), and two CD3ε chains (CD3E), plus the TCR (that can be α/β, or γ/δ type in the subsets of T cells named after the TCR they express) and the ζ-chain (zeta-chain).

CD3e plays a crucial role in T cell development, highlighted by the discovery that defects in CD3e cause severe immunodeficiency [8,22].

Therapeutic anti-CD3e monoclonal antibodies (mAbs) have been developed and investigated for clinically beneficial effects in autoimmune diseases (inflammatory bowel diseases [1,16] and type 1 diabetes [15,20]) and transplantation (graft-versus-host disease [5-6,29] and renal transplantation [19]) CD3e-targeting mAbs may be useful in combination with other therapies [2,9]. Anti-CD3e antibodies that are engineered to bind additional cellular targets and which selectively target the immune destruction of cancer cells are approved for use in immuno-oncology indications (e.g. blinatumomab and catumaxomab). Muromonab-CD3 was used to prevent rejection of organ allografts, but was withdrawn from the market due to lack of demand.

Cell Type Associations

Immuno Cell Type:

T cells

Immuno Process Associations

Immuno Process:

B cell (activation)

Immuno Process:

T cell (activation)

Immuno Process:

Immune regulation

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Immuno Disease Associations

Disease Name:	Acute lymphocytic leukemia (ALL)
Disease Synonyms:	no synonynms
Comment:	CD3e is the molecular target of approved drug blinatumomab, as a treatment Philadelphia chromosome-negative precursor B-cell ALL
Disease X-refs:	OMIM: 613065
References:

Clinically-Relevant Mutations and Pathophysiology

Disease:

Immunodeficiency 18; IMD18

Synonyms:	CD3epsilon deficiency [Disease Ontology: DOID:0060017] Immunodeficiency 18, SCID variant [OMIM: 615615] Immunodeficiency 18, Severe combined immunodeficiency variant [OMIM: 615615] Severe combined immunodeficiency [Orphanet: ORPHA183660] T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta [Orphanet: ORPHA169160]
Disease Ontology:	DOID:0060017
OMIM:	615615
Orphanet:	ORPHA169160, ORPHA183660

References

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1. Ahluwalia JP. (2012) Immunotherapy in inflammatory bowel disease. Med Clin North Am, 96 (3): 525-44, x. [PMID:22703854]

2. Besançon A, Goncalves T, Valette F, Dahllöf MS, Mandrup-Poulsen T, Chatenoud L, You S. (2018) Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice. Diabetologia, 61 (2): 389-398. [PMID:29030662]

3. Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H. (1993) The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol, 23 (2): 403-11. [PMID:8436176]

4. Borroto A, Reyes-Garau D, Jiménez MA, Carrasco E, Moreno B, Martínez-Pasamar S, Cortés JR, Perona A, Abia D, Blanco S et al.. (2016) First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases. Sci Transl Med, 8 (370): 370ra184. [PMID:28003549]

5. Carpenter PA, Appelbaum FR, Corey L, Deeg HJ, Doney K, Gooley T, Krueger J, Martin P, Pavlovic S, Sanders J et al.. (2002) A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood, 99 (8): 2712-9. [PMID:11929757]

6. Carpenter PA, Lowder J, Johnston L, Frangoul H, Khoury H, Parker P, Jerome KR, McCune JS, Storer B, Martin P et al.. (2005) A phase II multicenter study of visilizumab, humanized anti-CD3 antibody, to treat steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant, 11 (6): 465-71. [PMID:15931635]

7. Chau LA, Tso JY, Melrose J, Madrenas J. (2001) HuM291(Nuvion), a humanized Fc receptor-nonbinding antibody against CD3, anergizes peripheral blood T cells as partial agonist of the T cell receptor. Transplantation, 71 (7): 941-50. [PMID:11349730]

8. de Saint Basile G, Geissmann F, Flori E, Uring-Lambert B, Soudais C, Cavazzana-Calvo M, Durandy A, Jabado N, Fischer A, Le Deist F. (2004) Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J Clin Invest, 114 (10): 1512-7. [PMID:15546002]

9. Dean Y, Dépis F, Kosco-Vilbois M. (2012) Combination therapies in the context of anti-CD3 antibodies for the treatment of autoimmune diseases. Swiss Med Wkly, 142: w13711. [PMID:23254986]

10. Dreier T, Lorenczewski G, Brandl C, Hoffmann P, Syring U, Hanakam F, Kufer P, Riethmuller G, Bargou R, Baeuerle PA. (2002) Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int J Cancer, 100 (6): 690-7. [PMID:12209608]

11. Engelberts PJ, Hiemstra IH, de Jong B, Schuurhuis DH, Meesters J, Beltran Hernandez I, Oostindie SC, Neijssen J, van den Brink EN, Horbach GJ et al.. (2020) DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine, 52: 102625. [PMID:31981978]

12. Giffin MJ, Cooke K, Lobenhofer EK, Estrada J, Zhan J, Deegen P, Thomas M, Murawsky CM, Werner J, Liu S et al.. (2021) AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clin Cancer Res, 27 (5): 1526-1537. [PMID:33203642]

13. Goldstein G. (1987) Overview of the development of Orthoclone OKT3: monoclonal antibody for therapeutic use in transplantation. Transplant Proc, 19 (2 Suppl 1): 1-6. [PMID:3105134]

14. Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, Rattel B, Adam PJ, Anderson KC, Friedrich M. (2017) A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia, 31 (8): 1743-1751. [PMID:28025583]

15. Kaufman A, Herold KC. (2009) Anti-CD3 mAbs for treatment of type 1 diabetes. Diabetes Metab Res Rev, 25 (4): 302-6. [PMID:19319985]

16. Kawalec P, Mikrut A, Łopuch S. (2014) Systematic review of the effectiveness of biological therapy for active moderate to severe ulcerative colitis. J Gastroenterol Hepatol, 29 (6): 1159-70. [PMID:24955447]

17. Linke R, Klein A, Seimetz D. (2010) Catumaxomab: clinical development and future directions. MAbs, 2 (2): 129-36. [PMID:20190561]

18. Mathur D, Root AR, Bugaj-Gaweda B, Bisulco S, Tan X, Fang W, Kearney JC, Lucas J, Guffroy M, Golas J et al.. (2020) A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers. Clin Cancer Res, 26 (9): 2188-2202. [PMID:31996389]

19. Norman DJ, Vincenti F, de Mattos AM, Barry JM, Levitt DJ, Wedel NI, Maia M, Light SE. (2000) Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. Transplantation, 70 (12): 1707-12. [PMID:11152101]

20. Phillips B, Trucco M, Giannoukakis N. (2011) Current state of type 1 diabetes immunotherapy: incremental advances, huge leaps, or more of the same?. Clin Dev Immunol, 2011: 432016. [PMID:21785616]

21. Popma SH, Griswold DE, Li L. (2005) Anti-CD3 antibodies OKT3 and hOKT3gamma1(Ala-Ala) induce proliferation of T cells but impair expansion of alloreactive T cells; aspecifc T cell proliferation induced by anti-CD3 antibodies correlates with impaired expansion of alloreactive T cells. Int Immunopharmacol, 5 (1): 155-62. [PMID:15589476]

22. Soudais C, de Villartay JP, Le Deist F, Fischer A, Lisowska-Grospierre B. (1993) Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nat Genet, 3 (1): 77-81. [PMID:8490660]

23. Sun LL, Ellerman D, Mathieu M, Hristopoulos M, Chen X, Li Y, Yan X, Clark R, Reyes A, Stefanich E et al.. (2015) Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med, 7 (287): 287ra70. [PMID:25972002]

24. Trajkovic V. (2002) Nuvion. Protein Design Labs. Curr Opin Investig Drugs, 3 (3): 411-4. [PMID:12054088]

25. Tso JY, Cole MS, Anasetti C. (1998) Mutated nonactivating IgG2 domains and anti CD3 antibodies incorporating the same. Patent number: US5834597. Assignee: Protein Design Labs Inc. Priority date: 20/05/1996. Publication date: 10/11/1998.

26. Van Loo PF, Doornbos R, Dolstra H, Shamsili S, Bakker L. (2015) Preclinical Evaluation of MCLA117, a CLEC12AxCD3 Bispecific Antibody Efficiently Targeting a Novel Leukemic Stem Cell Associated Antigen in AML. Blood, 126 (23): 325.

27. Xu D, Alegre ML, Varga SS, Rothermel AL, Collins AM, Pulito VL, Hanna LS, Dolan KP, Parren PW, Bluestone JA et al.. (2000) In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol, 200 (1): 16-26. [PMID:10716879]

28. Xu G, Qian N, Liu Y, Li H, Yang C, Wang J, Wang F, Chen L, Bai G, Xu Q et al.. (2022) Preclinical characterization of a Fab-like CD3/CLDN18.2 XFab® bispecific antibody against solid tumors. Immunobiology, 227 (6): 152283. [PMID:36198215]

29. Yu XZ, Bidwell SJ, Martin PJ, Anasetti C. (2001) Anti-CD3 epsilon F(ab')2 prevents graft-versus-host disease by selectively depleting donor T cells activated by recipient alloantigens. J Immunol, 166 (9): 5835-9. [PMID:11313428]