Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJVYO3)

• DTT Name: Myeloid cell surface antigen CD33 (CD33)
• Synonyms: Siglec-3; Sialic acid-binding Ig-like lectin 3; SIGLEC3; Gp67
• Gene Name: CD33
• DTT Type: Successful target; [1]
• BioChemical Class: Immunoglobulin
• UniProt ID: CD33_HUMAN
• TTD ID: T38950
• Sequence:
  MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYW
  FREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRM
  ERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWL
  SAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTT
  GIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTH
  PTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSE
  VRTQ
• 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.
• KEGG Pathway: Hematopoietic cell lineage (hsa04640)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Gemtuzumab ozogamicin	DMJ2O7B	Acute myeloid leukaemia	2A60	Approved	[1]

24 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Vadastuximab talirine	DM9LH10	Acute myeloid leukaemia	2A60	Phase 3	[2]
Actimab-A	DMKBIPR	Acute myeloid leukaemia	2A60	Phase 2	[2]
Actimab-MDS	DMP8EEX	Myelodysplastic syndrome	2A37	Phase 2	[3]
BI-836858	DMUVMY9	Myelodysplastic syndrome	2A37	Phase 2	[4]
Anti-CD33 CAR-T cells	DM9NPF6	Myeloid leukaemia	2B33.1	Phase 1/2	[5]
CART33 cells	DM81JIT	Myeloid leukaemia	2B33.1	Phase 1/2	[6]
CD33-specific gene-engineered T cells	DMM35D2	Acute myeloid leukaemia	2A60	Phase 1/2	[7]
GTB-3550	DMK2RIB	Acute myelogenous leukaemia	2A41	Phase 1/2	[8]
HuM-195-Ac-225	DMIU1HY	Acute myelogenous leukaemia	2A41	Phase 1/2	[9]
SGN-CD33A	DMRC7PI	Acute myeloid leukaemia	2A60	Phase 1/2	[10]
225Ac-labelled aCD33	DM2SQBF	Acute myeloid leukaemia	2A60	Phase 1	[11]
Actimab-M	DM5KMYQ	Multiple myeloma	2A83	Phase 1	[2]
AL003	DMF6W5K	Alzheimer disease	8A20	Phase 1	[12]
Allogeneic CART-33	DM4RHM5	Myeloid leukaemia	2B33.1	Phase 1	[13]
AMG 330	DMC3G2E	Acute myeloid leukaemia	2A60	Phase 1	[14]
AMG 673	DMA3B9T	Acute myeloid leukaemia	2A60	Phase 1	[15]
AMV564	DMT27PA	Acute myeloid leukaemia	2A60	Phase 1	[16]
CART-33 cells	DMBHCSL	Acute myeloid leukaemia	2A60	Phase 1	[17]
CD123-CD33 Ccar	DMUJF9T	Acute myeloid leukaemia	2A60	Phase 1	[18]
CD33-CAR-T Cell	DMYD31U	Acute myeloid leukaemia	2A60	Phase 1	[19]
CLL1-CD33 cCART cell therapy	DM5EM04	Acute myeloid leukaemia	2A60	Phase 1	[18]
GEM333	DMDMKVL	Acute myeloid leukaemia	2A60	Phase 1	[20]
HuM195/rGel	DMDZBTY	leukaemia	2A60-2B33	Phase 1	[21]
JNJ-67571244	DMQOHRA	Acute myeloid leukaemia	2A60	Phase 1	[22]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lintuzumab	DMD39G4	leukaemia	2A60-2B33	Discontinued in Phase 2	[23]
HuM-195-Bi-213	DM9AOJT	Acute myeloid leukaemia	2A60	Discontinued in Phase 1/2	[24]
Oncolysin M	DM47ELH	leukaemia	2A60-2B33	Discontinued in Phase 1	[25]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CAR-T cells targeting CD33	DMH7BT9	Acute myeloid leukaemia	2A60	Preclinical	[26]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	5.37E-13	0.58	1.13

References

• [1] Targeted treatment of acute myeloid leukemia in older adults: role of gemtuzumab ozogamicin. Clin Interv Aging. 2009;4:197-205.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of Actinium Pharmaceuticals
• [4] The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev. 2014 Jul;28(4):143-53.
• [5] ClinicalTrials.gov (NCT03638206) Autologous CAR-T/TCR-T Cell Immunotherapy for Malignancies
• [6] ClinicalTrials.gov (NCT01864902) Treatment of Relapsed and/or Chemotherapy Refractory CD33 Positive Acute Myeloid Leukemia by CART-33
• [7] ClinicalTrials.gov (NCT03222674) Multi-CAR T Cell Therapy for Acute Myeloid Leukemia
• [8] Clinical pipeline report, company report or official report of GT Biopharma.
• [9] J Clin Oncol 29: 2011 (suppl; abstr 6516).
• [10] 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.
• [11] Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020 Sep;19(9):589-608.
• [12] A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol. 2020 Mar 31;11:456.
• [13] ClinicalTrials.gov (NCT02799680) Allogeneic CART-33 for Relapsed/Refractory CD33+ AML
• [14] 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.
• [15] Clinical pipeline report, company report or official report of Amgen.
• [16] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [17] ClinicalTrials.gov (NCT03291444) CAR-T Cells Combined With Peptide Specific Dendritic Cell in Relapsed/Refractory Leukemia/MDS
• [18] Clinical pipeline report, company report or official report of iCell Gene Therapeutics.
• [19] 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
• [20] Clinical pipeline report, company report or official report of Gemoab.
• [21] 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.
• [22] Clinical pipeline report, company report or official report of Genmab.
• [23] 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.
• [24] 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.
• [25] US patent application no. 6,926,898, Albumin fusion proteins.
• [26] ClinicalTrials.gov (NCT03473457) CAR-T Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia