Targeting the alpha subunit of IL-3 receptor (CD123) in patients with acute leukemia

Figures & data

Table 1. A comparison of CD123-targeting therapies

Class	Conjugated antibodies	Bispecific antibodies	CAR T cells
Availability for administration	Immediate, off-the-shelf product and not patient specific	Immediate, off-the-shelf product and not patient specific	Requiring manufacturing, however, off-the-shelf allogeneic CARs are in development
Method of administration	IV at repeated doses	Varies from continuous IV infusion to long half-life BiTEs given as repeated IV dosing	Usually single IV infusion
Lymphodepletion	Not required	Not required	This is usually required
FDA approval	Only tagraxofusp is approved for BPDCN	None yet	None yet
Stages in clinical studies	Varied from phase 1 studies to phase 1b/II studies (IMGN632)	Varied from phase 1 (JNJ-63709178, APVO436, XmAb14045) to phase 2/registry studies (flotetuzumab)	Early phases
In combination therapy	Actively being tested (tagraxofusp or IMNG632 in combination venetoclax + HMA)	Actively being tested (flotetuzumab + MGA012)	No, but dual “multi-target” CAR T cells are being tested
Main toxicity	VOD, CLS	CRS	CRS
Product half-life	Intermediate to long	Usually very short, although, there are long half BiTEs (XmAb14045)	Usually long but depends on the co-stimulatory domain and other characteristics

BiTE, bispecific T cell engager; BPDCN, blastic plasmacytoid dendritic cell neoplasm; CAR, chimeric antigen receptor; CLS, capillary leak syndrome; CRS, cytokine release syndrome; HMA, hypomethylating agent; IV, intravenous; VOD, veno-occlusive disease.

Table 2. Ongoing immunotherapy studies targeting CD123 in acute leukemia

Drug/study	NCT; Sponsor	Disease	Study phase	Status	Prelim results
Monoclonal antibodies and antibody-drug conjugates
Tagraxofusp (STML-401-0114)	NCT02113982; Stemline Therapeutics, Inc.	BPDCN, AML	1/2	Active, not recruiting	BPDCN cohort: ORR 90%; Pemmaraju et al 2019 N Engl J Med
Tagraxofusp with Azacitidine or Azacitidine/Venetoclax	NCT03113643; Dana-Farber Cancer Institute	AML, MDS	1	Recruiting	NA
IMGN623	NCT03386513; ImmunoGen, Inc.	r/r AML, BPDCN, ALL, Other CD123+ Hem Malignancies	1/2	Recruiting	AML cohort: ORR 18% BPDCN cohort: ORR 43%; Daver, Montesinos et al 2019 Blood
IMGN623 as monotherapy or with Venetoclax and/or Azacitidine	NCT04086264; ImmunoGen, Inc.	AML	1b/2	Recruiting	Daver, Papadantonakis et al 2019 Blood
Bispecific antibodies
Flotetuzumab	NCT02152956; MacroGenics	AML/hrMDS	1/2 (Expansion)	Enrolling	Uy et al 2019 Blood
Flotetuzumab	NCT03739606; City of Hope Medical Center	CD123+ hematological malignancies	2	Not recruiting yet	NA
XmAb14045	NCT02730312; Xencor, Inc.	r/r CD123-expressing hematological malignancies	1 (Expansion in r/r AML)	Enrolling	Ravandi et al 2018 Blood
JNJ-63709178	NCT02715011; Janssen	r/r AML	1	Recruiting	NA
Apvo436	NCT03647800; Aptevo	AML/MDS	1/1b	Recruiting	NA
Chimeric antigen receptor T cells
Autologous CD123CAR T cells	NCT02159495; City of Hope Medical Center	AML, BPDCN	1	Recruiting	Budde et al 2017 Blood
Redirected CD123 Autologous T cells	NCT03766126; University of Pennsylvania	AML	1	Recruiting	NA
MB-102 (autologous CD123 CAR T cells)	NCT04109482; Mustang Bio	AML, BPDCN, hrMDS	1/2	Recruiting	NA
UCART123/AMELI-01 (allogeneic CD123 CAR T cells)	NCT03190278; Cellectis S.A.	r/r AML	1	Recruiting	NA
Donor-derived CD123 CAR T cells	NCT03114670; Affiliated Hospital to Academy of Military Medical Sciences, China	r AML post alloHCT	1	Recruiting	NA
CD123/CLL1 bispecific CAR T cells	NCT03631576; Fujian Medical University, China	r/r AML	2/3	Recruiting	NA
CAR-T cells targeting CD123	NCT03796390; Hebei Senlang Biotechnology Inc., Ltd., China	AML	1	Recruiting	NA

ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; alloHCT: allogeneic hematopoietic cell transplantation; BPDCN: blastic plasmacytoid dendritic cell neoplasm; hrMDS: high-risk myelodysplastic syndrome; MDS: myelodysplastic syndrome; NA: not available; ORR: overall response rate; r: relapsed; r/r: relapsed or refractory.

Figure 1. Schematic of the modalities used to target CD123

CD123+ leukemia cells can be targeted and killed by (A) monoclonal antibodies (mAb) or antibody-drug conjugates (ADC) that induce antibody-dependent cytotoxicity and/or apoptosis, (B) bispecific antibodies that link a CD123-targeting domain to a T-cell engaging CD3-targeting domain and (C) Chimeric antigen receptor (CAR) T cells that couple a CD123-targeting domain to the effector function of T cells.