vibecotamab (XmAb14045) / Xencor, UT MD Anderson Cancer Center - LARVOL DELTA

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML (ASH 2023) - "Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Cardiovascular • Chronic Myelomonocytic Leukemia • Congestive Heart Failure • Heart Failure • Myelodysplastic Syndrome • Transplantation • CD123 • IL3RA • TP53

Single-arm, single-center, exploratory study of Vibecotamab combined with TAS-102 in the treatment of relapsed/metastatic RAS wild-type colorectal cancer patients who have failed second-line standard therapy (ChiCTR) - P=N/A | N=31 | Not yet recruiting | Sponsor: Shanghai East Hospital; Shanghai East Hospital

IO biomarker • New trial • Colorectal Cancer • Oncology • Solid Tumor • CTCs • PD-L1

Phase Ⅲ Clinical Study on the Efficacy and Safety of SBRT Combined With Vibecotamab in EGFR-Positive Metastatic Tumor Patients With Oligometastases (ChiCTR) - P3 | N=200 | Recruiting | Sponsor: Fifth Affiliated Hospital, Sun Yat-Sen University; Fifth Affiliated Hospital, Sun Yat-Sen University

New P3 trial • Oncology • Solid Tumor • EGFR

Updated Results from a Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML (ASH 2024) - "In the MDS/CMML cohort (16 MDS, 3 CMML), 9 pts (47%) received ≥2 prior lines of therapy, 11 pts (58%) had prior venetoclax exposure, and 2 pts (11%) had prior stem cell transplant (SCT). The protocol has now been amended for vibecotamab to be given indefinitely to responders. The clinical activity of vibecotamab, including in high-risk pts and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • IL3RA • TP53

A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure. (ASCO 2023) - P2 | "The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813."

Minimal residual disease • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome • CD123

Vibecotamab for measurable residual disease in acute myeloid leukemia and for myelodysplastic syndromes and chronic myelomonocytic leukemia after hypomethylating agent failure: a phase II study. (PubMed, J Hematol Oncol) - P2 | "Vibecotamab was active in low-blast myeloid diseases, although the durability of responses was modest. Additional studies of CD123-targeting bispecific antibodies, alone or in combination, are warranted for these diseases."

Journal • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD123 • IL3RA

NCI-2022-02215: A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=51 | Terminated | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2026 ➔ May 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2026 ➔ May 2026; <75% participation

Minimal residual disease • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • IL3RA

The rise of bispecific antibodies for dual targeting, singular impact: technology and clinical advancements. (PubMed, Int Immunopharmacol) - "Clinical candidates such as blinatumomab, HPN328, and XmAb14045 demonstrate the therapeutic potential and versatility of BsAbs, several of which have progressed to advanced stages of clinical trials or received regulatory approval. Their ability to orchestrate complex biological interactions with high specificity positions them at the forefront of next-generation biologic. This article explores the technical advancements and clinical milestones that underscore the rising impact of BsAbs in modern medicine."

Journal • Review • Immunology • Infectious Disease • Oncology

Vebectotamab Vedotin Combined With Pucotelimab in the Treatment of Locally Advanced Laryngeal Carcinoma (clinicaltrials.gov) - P1/2 | N=10 | Not yet recruiting | Sponsor: Tang-Du Hospital

New P1/2 trial • Head and Neck Cancer • Laryngeal Cancer • Oncology • Solid Tumor

Efficacy and Safety of SBRT Combined With Becotatug Vedotin in EGFR-Positive Metastatic Tumor Patients With Oligometastases (clinicaltrials.gov) - P3 | N=200 | Not yet recruiting | Sponsor: Ming-Yuan Chen

New P3 trial • Oncology • EGFR

Current status and future potential of CD123-based targeted therapies for acute leukemia. (PubMed, Expert Opin Biol Ther) - "It discusses completed and ongoing clinical trials for agents such as tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR T-cell therapies (e.g. MB-102, UCART123v1.2). While clinical activity has been demonstrated, especially in BPDCN, therapeutic durability and safety remain hurdles. Precision in antigen targeting, combination strategies, and toxicity management will be critical for successful integration of CD123-directed therapies into standard clinical practice."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

CSF1R Targeting T Cell Engaging Bispecific Antibodies Enable Safe and Efficient Immunotherapies in Acute Myeloid Leukemia (ASH 2024) - "While the use of T cell engaging bispecific antibodies (TCE) targeting B cell lineage antigens such as CD19 (Blinatumomab) or CD20 (Epcoritamab, Glofitamab, Mosuenetuzumab) have induced strong and long-lasting response rates in B cell malignancies (Falchi, Vardhana et al...Early clinical trials of CD33-TCE (JNJ-67571244, AMG330) or CD123-TCE (Vibecotamab) have shown modest clinical activity (response rates ranging between 0 to 16,6%) and a high degree of treatment-emergent adverse events (TEAE) (Ravandi, Bashey et al...In summary, we could show the safety and efficacy of CSF1R-TCB in preclinical in vitro and in vivo models and demonstrate the superior safety profile of CSF1R-TCB compared to CD33-TCB in CB-humanized mouse models. In cell line-derived xenograft models of AML, CSF1R-TCB induced anti-leukemia activity, warranting further preclinical and clinical investigations."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CCL3 • CD123 • CD20 • CD33 • CD34 • CSF1R • CSF2 • IL2 • IL3RA • IL6

CSF1R Targeting T Cell Engaging Bispecific Antibodies Enable Safe and Efficient Immunotherapies in preclinical models of Acute Myeloid Leukemia (DGHO 2025) - "Early trials of CD33-TCEs (JNJ-67571244, AMG330) and CD123-TCEs (Vibecotamab) demonstrated modest activity (0–16.6% response rates) and frequent treatment-emergent adverse events...Whether CSF1R can be effectively targeted by TCEs remained unclear.We developed a CSF1R-targeted TCE (CSF1R-TCE) using CrossMAb® 2+1 TCE format (as used in FDA and EMA-approved Glofitamab) and demonstrated efficacy in vitro and in vivo...Importantly, utilizing a CD34+ cord blood (CB) stem cell-humanized mouse model, CSF1R-TCE led to lower cytokine release and minimal reduction in HSPC counts compared to CD33-TCE (p < 0.01 for GMCSF, MIP1a; p < 0.05 for IL2, IL6, MCP1 and MIP1b detected in serum 24 hours after therapy). In xenograft models using luciferase-labeled Mv4-11 cells, CSF1R-TCE with T cells reduced tumor growth vs. control TCE (p < 0.0001 by day 38).In summary, we could show the safety and efficacy of CSF1R-TCE in preclinical in vitro and in vivo models and demonstrate..."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CCL3 • CD123 • CD33 • CD34 • CSF1R • CSF2 • IL2 • IL3RA • IL6

INCA035784, A NOVEL, EQUIPOTENT T CELL–REDIRECTING ANTIBODY FOR PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS CARRYING DIFFERENT TYPES OF CALRETICULIN MUTATIONS (EHA 2025) - "INCA035784 does not bind to wtCALR when a stress agent such as doxorubicin induces its translocation to the cell surface...INCA035784 induced minimal levels of CRS-associated cytokines from HD PBMCs, HD T cells, and patient-derived PBMCs vs other T cell-engaging antibodies such as mosunetuzumab and vibecotamab, targeting CD20 and CD123, respectively... Overall, INCA035784 activates T cells in the presence of mutCALR complexed with TPOR on the cell surface. By binding to a unique, conserved epitope on the mutCALR N-domain, INCA035784 can target the diverse mutCALR variants found across the MPN patient population. INCA035784 also exhibits a low-risk profile with respect to cytokine induction."

Clinical • Myeloproliferative Neoplasm • Oncology • CALR • CD123 • CD34 • CD69 • IL2RA • IL3RA • MPL

NCI-2022-02215: A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Minimal residual disease • Acute Myelogenous Leukemia • Myelodysplastic Syndrome • IL3RA

Bispecific antibodies in immunotherapy for acute leukemia: latest updates from the 66th annual meeting of the American society of hematology, 2024. (PubMed, Front Oncol) - "Blinatumomab plus standard chemotherapy or in combination with other treatments, such as Mini-Hyper-CVD and Inotuzumab Ozogamicin, improved disease-free survival (DFS) in B-ALL. In AML and related conditions, novel BsAbs like AFM28 (CD123xCD16A) and Vibecotamab (CD123xCD3) showed promising efficacy in heavily pretreated R/R AML and in MDS/CMML following the failure of treatment with hypomethylating agents (HMA). The meeting underscored the transformative potential of BsAbs, especially in ALL-focused trials, with ongoing research aiming to evaluate their safety and efficacy in broader patient populations and combination regimens. This summary highlights the latest progress in BsAb-based immunotherapy presented at the ASH 2024 meeting, held from December 7-10 in San Diego, California."

IO biomarker • Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IL3RA

CSF1R-targeting T cell engaging bispecific antibodies for Acute Myeloid Leukemia treatment (ITOC 2025) - "Background The potential of T-cell engaging bispecific antibodies (TCEs) is illustrated by the success of targeting CD19 (Blinatumomab) and CD20 (Epcoritamab, Glofitamab, Mosuenetuzumab) in relapsed and refractory B-cell non-Hodgkin lymphoma. However, in AML, TCEs targeting CD33 (JNJ-67571244, AMG330) and CD123 (Vibecotamab) have shown low efficacy and high toxicity...Consistent with our single-cell RNA sequencing-based target analysis, the CSF1R-TCE exhibited a superior safety profile than the CD33-TCE while maintaining anti-tumor activity. CSF1R-targeting TCEs may represent a novel immunotherapeutic approach for AML with high translative potential."

Acute Myelogenous Leukemia • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD123 • CD33 • CD34 • CSF1R • IL3RA

Vibecotamab shows promise in high-risk leukemia and myeloid diseases (Newswise) - P2 | N=42 | NCT05285813 | "The Phase II study treated 37 patients with low-blast myeloid diseases from two groups: one with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), and the other with measurable residual disease (MRD)-positive acute myeloid leukemia (AML). In the MDS/CMML group, 68% of patients responded to vibecotamab. Among patients with MRD-positive AML, 28% achieved MRD negativity, with some responses ongoing for over two years. All responses were observed after the first cycle of therapy."

P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome

Phase 1 Study of Vibecotamab Identifies an Optimized Dose for Treatment of Relapsed/Refractory Acute Myeloid Leukemia (Cancer Network) - P1 | N=120 | NCT02730312 | Sponsor: Xencor, Inc. | "A phase 1 clinical trial, published in the journal Blood Advances, has found the optimal dosing schedule with a tolerable safety profile in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML)....Vibecotamab showed preliminary antileukemic activity, with a total of 10 responders achieving complete remission (CR), CR with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS), resulting in an overall response rate (ORR) of 9.0%. The incidence and grade of CRS were highest during the first dose and weekly step-up dosing. Peak levels of the cytokine IL-6 correlated with higher priming doses and weekly dosing step-ups."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

MD Anderson Research Highlights: ASH 2023 Special Edition (Newswise) - P2 | N=40 | NCT05285813 | "In a Phase II trial led by Nicholas Short, M.D., and presented by Daniel Nguyen, M.D., Ph.D., researchers evaluated vibecotamab in 11 patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents, as well as in 12 patients with measurable residual disease (MRD)-positive AML. Vibecotamab had a response rate of 64% in patients with MDS/CMML, while 25% of patients with MRD-positive AML achieved MRD negativity. Ten (44%) patients experienced grade 2 infusion reactions and one (4%) experienced a grade 3 infusion reaction. This study suggests vibecotamab is safe and merits further investigation as part of a combination therapy for patients with AML, MDS and CMML."

P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Phase 1 study of vibecotamab identifies an optimized dose for treatment of relapsed/refractory acute myeloid leukemia. (PubMed, Blood Adv) - P1 | "Response was associated with lower baseline blast count in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

Plasmacytoid dendritic cell neoplasms. (PubMed, Blood Res) - "Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms."

IO biomarker • Journal • Review • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD4 • NCAM1 • NRP1 • TCF4

Preclinical Characterization of NGM936, a Novel Bispecific T Cell Engager Targeting ILT3 for the Treatment of Acute Myeloid Leukemia with Monocytic Differentiation (ASH 2022) - "In both whole blood cytokine release assays and in TDCC assays in which cytokine secretion was measured after target engagement, induction of TNF-α, IL-6, IFN-γ, and IL-2 by NGM936 was considerably lower than that induced by a vibecotamab biosimilar (CD123 x CD3). Finally, NGM936 induced a dose-dependent depletion of circulating tumor cells in a xenograft model in which irradiated, immunodeficient NSG mice were engrafted with human PBMCs and human ILT3+ AML cells. NGM936 thus represents a promising new treatment strategy for monocytic AML, with the potential to eliminate monocytic leukemia cells while minimizing the myelotoxicity associated with ablation of healthy bone marrow."

Preclinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD34 • CTCs • IFNG • IL2 • IL6 • TNFA

A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2022 ➔ May 2022

Enrollment open • Minimal residual disease • Trial initiation date • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

A Phase II Study of Vibecotamab (XmAb14045) for MRD- Positive AML and MDS After Hypomethylating Agent Failure (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Minimal residual disease • New P2 trial • Acute Myelogenous Leukemia • Myelodysplastic Syndrome