Target Information

Target General Information

Top

Target ID

T38950 (Former ID: TTDS00091)

Target Name

Myeloid cell surface antigen CD33 (CD33)

Synonyms

Siglec-3; Sialic acid-binding Ig-like lectin 3; SIGLEC3; Gp67

Click to Show/Hide

Gene Name

CD33

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Acute myeloid leukaemia [ICD-11: 2A60]

Function

Preferentially recognizes and binds alpha-2,3- and more avidly alpha-2,6-linked sialic acid-bearing glycans. Upon engagement of ligands such as C1q or syalylated glycoproteins, two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in CD33 cytoplasmic tail are phosphorylated by Src-like kinases such as LCK. These phosphorylations provide docking sites for the recruitment and activation of protein-tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2. In turn, these phosphatases regulate downstream pathways through dephosphorylation of signaling molecules. One of the repressive effect of CD33 on monocyte activation requires phosphoinositide 3-kinase/PI3K. Sialic-acid-binding immunoglobulin-like lectin (Siglec) that plays a role in mediating cell-cell interactions and in maintaining immune cells in a resting state.

Click to Show/Hide

BioChemical Class

Immunoglobulin

UniProt ID

CD33_HUMAN

Sequence

MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYW
FREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRM
ERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWL
SAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTT
GIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTH
PTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSE
VRTQ

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T56X9Z

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 1 Approved Drugs

Gemtuzumab ozogamicin

Drug Info

Approved

Acute myeloid leukaemia

[2], [3]

Clinical Trial Drug(s)

[+] 24 Clinical Trial Drugs

Vadastuximab talirine

Drug Info

Phase 3

Acute myeloid leukaemia

[4]

Actimab-A

Drug Info

Phase 2

Acute myeloid leukaemia

[4], [5]

Actimab-MDS

Drug Info

Phase 2

Myelodysplastic syndrome

[6]

BI-836858

Drug Info

Phase 2

Myelodysplastic syndrome

[4], [5]

Anti-CD33 CAR-T cells

Drug Info

Phase 1/2

Myeloid leukaemia

[7]

CART33 cells

Drug Info

Phase 1/2

Myeloid leukaemia

[8]

CD33-specific gene-engineered T cells

Drug Info

Phase 1/2

Acute myeloid leukaemia

[9]

GTB-3550

Drug Info

Phase 1/2

Myelodysplastic syndrome

[10]

HuM-195-Ac-225

Drug Info

Phase 1/2

Acute myeloid leukaemia

[11]

SGN-CD33A

Drug Info

Phase 1/2

Acute myeloid leukaemia

[12]

225Ac-labelled aCD33

Drug Info

Phase 1

Acute myeloid leukaemia

[13]

Actimab-M

Drug Info

Phase 1

Multiple myeloma

[4]

AL003

Drug Info

Phase 1

Alzheimer disease

[14]

Allogeneic CART-33

Drug Info

Phase 1

Myeloid leukaemia

[15]

AMG 330

Drug Info

Phase 1

Acute myeloid leukaemia

[4], [5]

AMG 673

Drug Info

Phase 1

Acute myeloid leukaemia

[5]

AMV564

Drug Info

Phase 1

Acute myeloid leukaemia

[5]

CART-33 cells

Drug Info

Phase 1

Myelodysplastic syndrome

[16]

CD123-CD33 Ccar

Drug Info

Phase 1

Acute myeloid leukaemia

[17]

CD33-CAR-T Cell

Drug Info

Phase 1

Haematopoietic/lymphoid cancer

[18]

CLL1-CD33 cCART cell therapy

Drug Info

Phase 1

Acute myeloid leukaemia

[19]

GEM333

Drug Info

Phase 1

Acute myeloid leukaemia

[20]

HuM195/rGel

Drug Info

Phase 1

leukaemia

[21]

JNJ-67571244

Drug Info

Phase 1

Acute myeloid leukaemia

[22]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

Lintuzumab

Drug Info

Discontinued in Phase 2

leukaemia

[23], [24]

HuM-195-Bi-213

Drug Info

Discontinued in Phase 1/2

Acute myeloid leukaemia

[25]

Oncolysin M

Drug Info

Discontinued in Phase 1

leukaemia

[26]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

CAR-T cells targeting CD33

Drug Info

Preclinical

Acute myeloid leukaemia

[27]

Mode of Action

[+] 4 Modes of Action

Antagonist

[+] 1 Antagonist drugs

Vadastuximab talirine

Drug Info

[4]

Inhibitor

[+] 10 Inhibitor drugs

Actimab-A

Drug Info

[4]

GTB-3550

Drug Info

[33]

HuM-195-Ac-225

Drug Info

[34]

Actimab-M

Drug Info

[4]

AL003

Drug Info

[37]

AMG 330

Drug Info

[38]

AMG 673

Drug Info

[39]

GEM333

Drug Info

[40]

JNJ-67571244

Drug Info

[42]

HuM-195-Bi-213

Drug Info

[44]

CAR-T-Cell-Therapy

[+] 7 CAR-T-Cell-Therapy drugs

Anti-CD33 CAR-T cells

Drug Info

[7]

CART33 cells

Drug Info

[8]

CD33-specific gene-engineered T cells

Drug Info

[9]

Allogeneic CART-33

Drug Info

[15]

CART-33 cells

Drug Info

[16]

CD33-CAR-T Cell

Drug Info

[18]

CAR-T cells targeting CD33

Drug Info

[27]

Modulator

[+] 2 Modulator drugs

AMV564

Drug Info

[5]

Oncolysin M

Drug Info

[45]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

Top

Ligand Name: 2-aminoethyl 5-{[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)acetyl]amino}-3,5,9-trideoxy-9-[(4-hydroxy-3,5-dimethylbenzene-1-carbonyl)amino]-D-glycero-alpha-D-galacto-non-2-ulopyranonosyl-(2->6)-beta-D-galactopyranosyl-(1->4)-beta-D-glucopyranoside

Ligand Info

Structure Description

Cell Surface Receptor with Bound Ligand at 1.75-A Resolution

PDB:6D4A

Method

X-ray diffraction

Resolution

1.75 Å

Mutation

[46]

PDB Sequence

NFWLQVQESV

²⁹

TVQEGLCVLV

³⁹

PCTFFHPIPY

⁴⁹

YDKNSPVHGY

⁵⁹

WFREGAIISR

⁶⁹

DSPVATNKLD

⁷⁹

QEVQEETQGR

⁸⁹

FRLLGDPSRN

⁹⁹

NCSLSIVDAR

¹⁰⁹

RRDNGSYFFR

¹¹⁹

MERGSTKYSY

¹²⁹

KSPQLSVHVT

¹³⁹

DLT

Residue

Distance (Å)

PHE21

3.398

PRO46

4.433

PRO48

4.370

TYR50

3.418

PHE117

3.537

ARG119

2.736

SER124

4.475

Residue

Distance (Å)

THR125

4.247

LYS126

2.731

TYR127

3.738

SER128

2.726

TYR129

3.835

LYS130

3.507

GLN133

3.773

Click to View More Binding Site Information of This Target and Ligand Pair

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Myelin-associated glycoprotein (MAG)	PF08205 ; PF13927	30.120 (75/249)	5.88E-20
B-cell receptor CD22 (CD22)	PF08205 ; PF13895 ; PF13927 More >>	27.897 (65/233)	2.52E-14
Nephrin (NPHS1)	PF08205 ; PF00041 ; PF07679 ; PF13927 More >>	33.333 (32/96)	6.82E-04


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Hematopoietic cell lineage	hsa04640	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 1 KEGG Pathways

Hematopoietic cell lineage

Reactome

[+] 1 Reactome Pathways

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

References

Top

REF 1

Targeted treatment of acute myeloid leukemia in older adults: role of gemtuzumab ozogamicin. Clin Interv Aging. 2009;4:197-205.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6775).

REF 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

Clinical pipeline report, company report or official report of Actinium Pharmaceuticals

REF 7

ClinicalTrials.gov (NCT03638206) Autologous CAR-T/TCR-T Cell Immunotherapy for Malignancies

REF 8

ClinicalTrials.gov (NCT01864902) Treatment of Relapsed and/or Chemotherapy Refractory CD33 Positive Acute Myeloid Leukemia by CART-33

REF 9

ClinicalTrials.gov (NCT03222674) Multi-CAR T Cell Therapy for Acute Myeloid Leukemia

REF 10

ClinicalTrials.gov (NCT03214666) GTB-3550 (CD16/IL-15/CD33) Tri-Specific Killer Engager (TriKE) for High Risk Heme Malignancies. U.S. National Institutes of Health.

REF 11

Clinical pipeline report, company report or official report of Actinium Pharmaceuticals.

REF 12

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 13

ClinicalTrials.gov (NCT03705858) Actinium-225-Lintuzumab in Patients With Acute Myeloid Leukemia. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT03822208) A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Single and Multiple Doses of AL003 in Healthy Participants and in Participants With Mild to Moderate Alzheimer's Disease.. U.S.National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT02799680) Allogeneic CART-33 for Relapsed/Refractory CD33+ AML

REF 16

ClinicalTrials.gov (NCT03291444) CAR-T Cells Combined With Peptide Specific Dendritic Cell in Relapsed/Refractory Leukemia/MDS

REF 17

ClinicalTrials.gov (NCT04156256) CD123-CD33 cCAR in Patients With Relapsed and/or Refractory, High Risk Hematologic Malignancies. U.S. National Institutes of Health.

REF 18

ClinicalTrials.gov (NCT03126864) Study of Adoptive Cellular Therapy Using Autologous T Cells Transduced With Lentivirus to Express a CD33 Specific Chimeric Antigen Receptor in Patients With Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia

REF 19

Clinical pipeline report, company report or official report of iCell Gene Therapeutics.

REF 20

ClinicalTrials.gov (NCT03516760) Dose-escalating Phase I Trial With GEM333 in Patients With Acute Myeloid Leukemia. U.S. National Institutes of Health.

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007636)

REF 22

ClinicalTrials.gov (NCT03915379) A Study of JNJ-67571244 in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). U.S. National Institutes of Health.

REF 23

REF 24

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015937)

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008571)

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003885)

REF 27

ClinicalTrials.gov (NCT03473457) CAR-T Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia

REF 28

Deficient activation of Bak and Bax confers resistance to gemtuzumab ozogamicin-induced apoptotic cell death in AML. Exp Hematol. 2009 Jun;37(6):755-66.

REF 29

Successful treatment with gemtuzumab ozogamicin monotherapy in a pediatric patient with resistant relapse of acute myeloid leukemia. Turk J Pediatr. 2009 Jan-Feb;51(1):69-71.

REF 30

Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leuk... Int J Hematol. 2009 May;89(4):460-469.

REF 31

Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.

REF 32

The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev. 2014 Jul;28(4):143-53.

REF 33

Clinical pipeline report, company report or official report of GT Biopharma.

REF 34

J Clin Oncol 29: 2011 (suppl; abstr 6516).

REF 35

SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013 Aug 22;122(8):1455-63.

REF 36

Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020 Sep;19(9):589-608.

REF 37

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol. 2020 Mar 31;11:456.

REF 38

Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia. Mol Cancer Ther. 2014 Jun;13(6):1549-57.

REF 39

Clinical pipeline report, company report or official report of Amgen.

REF 40

Clinical pipeline report, company report or official report of Gemoab.

REF 41

Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies. Haematologica. 2013 Feb;98(2):217-21.

REF 42

Clinical pipeline report, company report or official report of Genmab.

REF 43

Phase III randomized multicenter study of a humanized anti-CD33 monoclonal antibody, lintuzumab, in combination with chemotherapy, versus chemotherapy alone in patients with refractory or first-relapsed acute myeloid leukemia. J Clin Oncol. 2005 Jun 20;23(18):4110-6.

REF 44

Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010 Nov 1;16(21):5303-11.

REF 45

US patent application no. 6,926,898, Albumin fusion proteins.

REF 46

Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Abeta Phagocytosis. iScience. 2019 Sep 27;19:110-118.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.

Prof. Feng ZHU

Prof. Yuzong CHEN