What are CD123 antibody-drug conjugates and why target CD123?
CD123 is a protein found on the surface of many blood cancer cells, including those in acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute lymphoblastic leukemia (ALL) [8][9]. It's an attractive target because it's often present at high levels on cancer cells but only at low levels on normal blood stem cells, meaning treatments can be directed at the cancer while sparing healthy tissue [8][6]. Antibody-drug conjugates (ADCs) are a type of targeted therapy that links a cancer-seeking antibody to a potent cell-killing drug; when the antibody binds to CD123 on a cancer cell, the ADC is internalized and releases the drug, killing the cell [1][4].
Several CD123 ADCs are in development, each with different payloads and linkers designed to improve efficacy and reduce side effects. For example, pivekimab sunirine (PVEK, formerly IMGN632) uses a DNA-alkylating payload [1][5], while VIP943 uses a kinesin spindle protein inhibitor and a unique linker that is only activated inside cancer cells [2][4]. Another, AZD9829, carries a topoisomerase I inhibitor [6]. The goal is to deliver a potent drug directly to the cancer cell, potentially improving outcomes while minimizing damage to healthy tissue.
What does the evidence show about improved outcomes?
The strongest evidence for improved outcomes comes from BPDCN, a rare and aggressive blood cancer. A long-term follow-up of a pivotal trial of tagraxofusp, a CD123-targeted therapy (not an ADC but a similar CD123-directed drug), showed that among 65 newly diagnosed patients, 75% responded, and 57% achieved a complete remission (CR) or clinical CR [3]. The median duration of response was 24.9 months, and the median overall survival was 15.8 months [3]. This led to FDA approval of tagraxofusp for BPDCN, making it the first approved CD123-targeted therapy [3].
For AML, the evidence is promising but still emerging. In a phase 1b/2 trial, adding pivekimab sunirine to the standard regimen of azacitidine and venetoclax in 50 newly diagnosed AML patients resulted in a complete remission rate of 52% and a composite CR rate of 66% [7]. Importantly, among those who achieved a CR, 73% became MRD-negative (no detectable leukemia cells), which is associated with better survival [7]. This was in a high-risk population, with 64% having adverse-risk genetics and 38% having TP53 mutations [7]. Preclinical studies also support the potential of CD123 ADCs: pivekimab sunirine showed profound activity in pediatric ALL patient-derived xenografts, with 26 of 37 models achieving maintained complete responses [5], and VIP943 showed complete tumor regression in 8 of 9 mice when combined with azacitidine and venetoclax in an AML model [4].
What are the challenges and limitations?
Despite the promise, there are significant challenges. One major concern is toxicity, particularly capillary leak syndrome, a potentially fatal side effect seen with tagraxofusp, which carries a black-box warning [3]. In the long-term BPDCN study, capillary leak syndrome occurred in 21% of patients, with 7% being grade 3 or higher [3]. Other side effects include myelosuppression (low blood counts), infections, and liver toxicity [7][4].
Another challenge is resistance. A study of pivekimab sunirine in pediatric ALL found that a patient-derived xenograft with very high CD123 expression was resistant to treatment because the antibody was not internalized, suggesting a novel resistance mechanism [1]. Similarly, in BPDCN, loss of CD123 antigen through genetic mechanisms was observed in one of three patient-derived xenografts treated with CD123 CAR T cells, another CD123-targeted approach [10]. These findings highlight that CD123 expression alone is not sufficient for response, and other factors, such as internalization and antigen stability, are critical [1][10].
Finally, while CD123 ADCs are being tested in clinical trials, many are still in early phases, and long-term data are limited. For example, VIP943 is in a phase 1 first-in-human trial, with dose escalation ongoing [2]. AZD9829 has shown preclinical activity but has not yet been tested in humans [6]. Thus, while the evidence is encouraging, the full impact on patient outcomes, especially in the long term, is not yet known.
About These Sources
This answer is built on 10 peer-reviewed studies — published from 2022 to 2025, 3 from 2024 or later, 8 in Q1 journals, collectively cited 181 times — selected as the most relevant from 13 studies that passed quality screening, drawn from 52 papers retrieved from a database of over 500 million.
Sources used in this answer
The CD123 antibody–drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia
In a preclinical study using 39 pediatric ALL patient-derived xenografts, pivekimab sunirine (PVEK) significantly extended event-free survival, especially in B-lineage ALL, but a xenograft with high CD123 expression was resistant due to failure of antibody internalization.
An open-label, multicenter phase 1 study to characterize safety, tolerability, preliminary antitumor activity, pharmacokinetics, and pharmacodynamics of VIP943 monotherapy in patients with advanced CD123+ hematologic malignancies.
This phase 1 trial (NCT06034275) is evaluating the safety and preliminary efficacy of VIP943, a CD123-targeted ADC with a novel legumain-cleavable linker and kinesin spindle protein inhibitor payload, in patients with relapsed/refractory CD123+ hematologic malignancies; dose escalation is ongoing.
CD123-Targeted Therapy Shows Long-Term Benefit for BPDCN Patients
In a long-term follow-up of a pivotal trial of tagraxofusp in BPDCN, 75% of 65 frontline patients responded, with 57% achieving complete remission; median duration of response was 24.9 months and median overall survival was 15.8 months, with capillary leak syndrome occurring in 21% of patients.
VIP943 Is a Novel CD123 Antibody Drug Conjugate with in Vitro and In Vivo Efficacy in Acute Myeloid Leukemia (AML) Models
Preclinical studies of VIP943 in AML models showed specific internalization, potent killing of leukemic stem cells, and complete tumor regression in 8/9 mice when combined with azacitidine and venetoclax, with a favorable safety profile in non-human primates.
Pediatric Preclinical Testing Consortium Evaluation of the Anti-CD123 Antibody-Drug Conjugate, IMGN632, Against Patient-Derived Xenograft Models of Pediatric Acute Lymphoblastic Leukemia
In a pediatric preclinical testing consortium study, IMGN632 (pivekimab sunirine) induced maintained complete responses in 26 of 37 pediatric ALL patient-derived xenografts, with significantly greater activity in B-lineage compared to T-lineage ALL.
First Disclosure of AZD9829, a TOP1i-ADC Targeting CD123: Promising Preclinical Activity in AML Models with Minimal Effect on Healthy Progenitors
AZD9829, a CD123-targeting ADC with a topoisomerase I inhibitor payload, showed robust in vitro and in vivo activity in AML models, including patient-derived xenografts, with minimal effects on healthy progenitors in preclinical studies.
Pivekimab Sunirine (PVEK, IMGN632), a CD123-Targeting Antibody-Drug Conjugate, in Combination with Azacitidine and Venetoclax in Patients with Newly Diagnosed Acute Myeloid Leukemia
In a phase 1b/2 trial of pivekimab sunirine plus azacitidine and venetoclax in 50 newly diagnosed AML patients, the complete remission rate was 52% and composite CR rate was 66%; 73% of responders achieved MRD negativity, with a manageable safety profile.
CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm
A review of CD123 as a therapeutic target in AML and BPDCN highlights that while CD123-targeting agents like tagraxofusp and IMGN632 show promise, therapeutic efficacy is still unsatisfactory and needs improvement through combination strategies.
Acute myeloid leukemia management and research in 2025
A 2024 review of AML management states that CD123 antibody-drug conjugates and other CD123-targeting antibodies are showing promising results in clinical trials, but they are not yet part of standard therapy.
Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells
In preclinical models of BPDCN, allogeneic anti-CD123 CAR T cells (UCART123) showed selective antitumor activity and eradicated disease in a subset of patient-derived xenografts, but antigen loss was observed in one of three models.