talacotuzumab (JNJ-56022473) / CSL Behring, J&J - LARVOL DELTA

A de novo designed miniprotein enables modular and specific CAR-T targeting (AACR 2025) - "In the same study, a talacotuzumab antibody based adapter molecule and a direct anti-CD123 CAR-T were used for comparison. The miniprotein-directed CAR exhibited multiple advantages over both the antibody and the direct CAR-T, including increased efficacy with lower dose required of both the adapter and the CAR-T cells, improved tumor occupation, and less CAR-T exhaustion.Our system combining a FITC-conjugated miniprotein with anti-FITC CAR-T cells yields complete remission in an MV-4-11 xenograft mice model, outperforming both an antibody adapter and direct CAR-T approaches. We demonstrated that the use of controllable CAR-T cells combined with miniprotein adapters exhibits an unprecedented potential for the design of dosable, redirectable and multiplexable cancer treatments."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

De Novo Design of a Miniprotein That Functions As an Adapter for CAR-T Cells and Enables Modular Tumor Targeting for the Treatment of AML (ASH 2024) - "In the same study, a talacotuzumab antibody based adapter molecule and a direct anti-CD123 CAR-T were used for comparison. The miniprotein-directed CAR exhibited multiple advantages over both the antibody and the direct CAR-T, including increased efficacy with lower dose required of both the adapter and the CAR-T cells, improved tumor occupation, and less CAR-T exhaustion.ConclusionsOur system combining a FITC-conjugated miniprotein with anti-FITC CAR-T cells yields complete remission in an MV-4-11 xenograft mice model, outperforming both an antibody adapter and direct CAR-T approaches. We demonstrated that the use of controllable CAR-T cells combined with miniprotein adapters exhibits an unprecedented potential for the design of dosable, redirectable and multiplexable cancer treatments."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • IL3RA

CSL362 potently and specifically depletes pDCs invitro and ablates SLE-immune complex-induced IFN responses. (PubMed, iScience) - "TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD123 • IFNA1

[VIRTUAL] FACT physical wellbeing to independently predict overall survival in patients with acute myeloid leukemia. (ASCO 2020) - P2/3 | " Data were from 317 AML patients unfit for intensive therapy from a clinical trial comparing Dacogen (decitabine) plus Talacotuzumab versus Dacogen (decitabine) alone (AML2002; NCT02472145). FACT-Leu scales, especially the PWB, were significant prognostic factors for OS among AML patients not suitable for intensive therapy. These results may indicate PROs' value as stratification factors in trials with AML patients and underscore the need to more systematically collect PRO data in routine care practice with AML patients. Research Funding: None"

Clinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Engineered Single Amino Acid Substitutions Protect Hematopoietic Stem and Progenitor Cells from CD123 Targeted Immunotherapy (ASH 2022) - "We used the known co-crystal structure of CD123 bound to the mAb CSL362 (talacotuzumab) for computer-aided protein engineering...Variant IL-3 receptor engineered HSPC's and paired immunotherapies could enable novel and targeted therapeutic interventions post HSCT to either treat minimal residual disease or be used as a salvage therapy. Such approaches could expand the therapeutic window and broaden indications and applications for targeted immunotherapies for various malignant and benign conditions."

IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD123 • CD34

Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia. (ASCO 2022) - "gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm...studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose...noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine...reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm...administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70)...reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%)... Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.AE: adverse events; GI:..."

Review • Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Malignancies • Inflammation • Leukemia • Oncology • CD123

Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) or Daratumumab in Transfusion-Dependent Participants With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Who Are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment (clinicaltrials.gov) - P2 | N=34 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia. (PubMed, Nat Commun) - "Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain...CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment...Functionally, the CTLA-4 anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 anti-CD123 CAR T cells."

CAR T-Cell Therapy • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • TNFA

SINGLE AGENT TALACOTUZUMAB IN ELDERLY HIGH-RISK MDS OR AML PATIENTS FAILING HYPOMETHYLATING AGENTS – RESULTS OF THE SAMBA STUDY BY THE EMSCO NETWORK (EHA 2018) - "Even though ADCC-mediated targeting of CD123 seems to be a promising treatment option, patients with advancedMDS/AML displayed significant alterations in their immune cell repertoire whichmay have contributed to the moderate clinical benefitwith single agent TAL treatment."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Anti-CD123 Targeted Therapy with Talacotuzumab in Advanced MDS and AML after Failing Hypomethylating Agents - Final Results of the Samba Trial (ASH 2018) - "Conclusion Single agent TAL has limited efficacy in patients with advanced myeloid malignancies failing HMA. Expression of CD123 on immature MDSCs might serve as a biomarker of response for future anti-CD123 targeted approaches."

Clinical • IO biomarker • PD(L)-1 Biomarker • Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Patient-reported outcomes predict overall survival in older patients with acute myeloid leukemia. (PubMed, J Geriatr Oncol) - P2/3 | "These results indicate PROs' value for predicting outcomes among older AML patients and underscore the need to more systematically collect PRO data in routine care with these patients. ClinicalTrials.gov Registration: NCT02472145."

Clinical • Journal • Patient reported outcomes • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) or Daratumumab in Transfusion-Dependent Participants With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Who Are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment (clinicaltrials.gov) - P2; N=34; Active, not recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Dec 2021 ➔ Aug 2021

Trial completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

[VIRTUAL] Novel Combination Drug Regimens Using Hypomethylating Agents in Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (ASH 2020) - "For patients who are not candidates for intensive chemotherapy, outcomes in terms of complete response/complete response with incomplete hematologic response (CR/CRi) and median overall survival (mOS) have been evaluated using hypomethylating agents(HMA) including azacytidine (AZA)(CR/CRi=18-27.8%, mOS=10.4-24.5 months) and decitabine (CR/CRi= 18-47%, mOS= 7-7.8 months)...Drugs used in combination included gemcitabine ozagamicin (n=40, CR/CRi =45%, mOS= 7 m), cladribine and low dose cytarabine (n=118, CR/CRi= 68%, mOS =13.8 m), vadastuximab talirine (n=53, CR/CRi=70%, mOS=11.3 m) and selinexor (n=5, CR/Cri= 80%) . In addition, three studies compared outcomes of CDR involving decitabine with all trans retinoic acid (ATRA)(n=93, ORR=21.9% vs 13.5%, p=0.06; mOS= 8.2 m vs 5.1 m, p=0.006) or talacotuzumab (CR/CRi= 15% vs 11%, p=0.44; mOS= 5.36 m vs 7.26 m, p=0.78) or bortezomib (CR/CRi= 39% vs 38%, p=0.91, mOS=9.3 m vs 8.9,p=0.18) to decitabine alone...Drugs included..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. (PubMed, Leukemia) - No abstract available

Clinical • Journal • Myelodysplastic Syndrome • Oncology

An Efficacy and Safety Study of Decitabine (DACOGEN) Plus JNJ-56022473 (Anti CD123) Versus Decitabine (DACOGEN) Alone in Participants With Acute Myeloid Leukemia (AML) Ineligible for Intensive Chemotherapy (clinicaltrials.gov) - P2/3; N=406; Recruiting; Sponsor: Janssen Research & Development, LLC; Phase classification: P2 ➔ P2/3

Phase classification • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Development of a novel fully-human anti-CD123 antibody to target acute myeloid leukemia. (PubMed, Leuk Res) - "Further, the two antibodies, when reformatted as bispecific BiTE™ reagents by fusion with the anti-CD3 scFv(OKT3) antibody fragment, induced selective killing of AML blasts by patient-derived, autologous T-cells in an in vitro setting, but BiTE(CSL362/OKT3) exhibited a 10-fold higher potency compared to BiTE(H9/OKT3). The availability of two classes of CD123-specific biopharmaceuticals, capable of redirecting the cytolytic activity of NK cells and T cells against AML blasts, may enable novel interventional strategies and combination opportunities for the treatment of AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Talacotuzumab: “Reduction in blast counts in peripheral blood after one dose” (Johnson and Johnson Ltd) - Pharmaceutical Business Review

Clinical data • Acute Myelogenous Leukemia

CSL: R&D Investor Briefing (CSL Behring) - “Manageable safety profile: Pre-medication with steroids required to prevent infusion reactions”; “PD effects confirming CD123-targeted ADCC”; “Rapid and full depletion of basophils and pDCs: Sustained depletion at CSL362 dose levels ≥ 3 mg/kg”; “Saturation of CD123 receptor on monocytes at CSL362 dose levels ≥ 3 mg/kg (trough concentration > 3μg/ml)”; “Conversion of MRD seen in a subset of pts treated with CSL362”

P1 data • Acute Myelogenous Leukemia

Talacotuzumab: Regulatory filing in US and EU for AML in 2018 (Johnson and Johnson Ltd) - Pharmaceutical Business Review 

BLA • European regulatory • Acute Myelogenous Leukemia

Comparison of an in vitro cytokine release model with in vivo serum cytokine responses in AML patients administered CSL362 in a Phase 1 study (CSLCT-AML-11-73) (ICI 2016) - "Acute myeloid leukemia (AML) patients administered CSL362 during a Phase 1 clinical study (CSLCT-AML-11-73) demonstrated transient elevation of seven (IL-6, IL-8, GM-CSF, IL-1RA, IFN-γ, IL-1β and TNF-α) of the eleven cytokines/chemokines detected with the in vitro assay. This study demonstrates that in vitro models can be used to assess the potential of therapeutic antibodies' to elicit in vivo cytokine responses in humans."

Preclinical • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. (PubMed, Leukemia) - "Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment."

Clinical • Journal • P2/3 data

Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) or Daratumumab in Transfusion-Dependent Participants With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Who Are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment (clinicaltrials.gov) - P2; N=34; Active, not recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Jan 2020 ➔ Jan 2021

Clinical • Trial completion date

Azacytidine Sensitizes AML Cells for Effective Elimination By CD123 CAR T-Cells (ASH 2019) - "Chimeric antigen receptor T-cells (CAR Tc) have yielded impressive remission rates in treatment-refractory B-cell malignancies (B-ALL and B-lymphomas) by targeting CD19, resulting in the first FDA approved CAR Tc therapies, Kymriah and Yescarta...The anti-CD123 CAR was constructed with the humanized CSL362-based ScFv and the CD28-OX40-CD3ζ signaling domain, encoded in a third-generation lentiviral vector and expressed in CD3+ Tc from healthy donors...This is the first demonstration that HMAs and CAR Tc immunotherapy can be used synergistically to treat AML. Considering HMAs are currently under clinical investigation in AML, our data encourage further clinical evaluation of this dual treatment in r/r AML, including high-risk patients that are chemotherapy or allogeneic transplantation ineligible."

CAR T-Cell Therapy • IO Biomarker • CD123 • CD8 • MLL • MLL2 • PD-L1

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1. (PubMed, Blood Cancer J) - "Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. Inhibition of the ARF6-PLD-1 axis (NAV2729), but not of the MAPK pathway (U0126), completely abrogated CSL362-facilitated antibody-dependent cell-mediated cytotoxicity (ADCC) in haNK and activated primary NK cells. Our results support CD123 as an immunotherapeutic target for HL and the combination of NK cells and CSL362 as a treatment strategy for HL."

IO Biomarker • Journal

Study to Separately Evaluate the Activity of Talacotuzumab (JNJ-56022473) or Daratumumab in Transfusion-Dependent Participants With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Who Are Relapsed or Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment (clinicaltrials.gov) - P2; N=34; Active, not recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Jan 2019 ➔ Jan 2020

Clinical • Trial completion date