Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment

Bonnevaux, Hélène; Guérif, S.; Albrecht, Julia N.; Jouannot, Erwan; Gallier, Thibaud De; Beil, Christian; Lange, Christian; Leuschner, Wulf Dirk; Schneider, Marion; Lemoine, C.; Caron, Anne; Amara, Céline; Barrière, Cédric; Siavellis, Justine; Bardet, Valérie; Luna, Ernesto; Agrawal, Pankaj B.; Drake, Donald R.; Rao, Ercole; Wonerow, Peter; Carrez, Chantal; Blanc, Véronique; Hsu, Karl; Wiederschain, Dmitri; Fraenkel, Paula G.; Virone-Oddos, Angela

doi:10.1080/2162402x.2021.1945803

Cited by 6 publications

(5 citation statements)

References 55 publications

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“…A single-dose exploratory study in healthy cynomolgous monkeys was performed to evaluate PK, PD, and toxicity of the CD33/CD123 NANOBODY TCE. Dose levels were determined based on earlier studies with CD123/CD3 TCE 37 : 0.04 μg/kg and 0.4 μg/kg (2 animals per dose level). A favorable PK profile was observed with half-life determined at 1.1 to 1.4 days indicating some target-mediated drug disposition ( Figure 7 A; supplemental Table 6 ).…”

Section: Resultsmentioning

confidence: 99%

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Dual-targeting CD33/CD123 NANOBODY T-cell engager with potent anti-AML activity and good safety profile

Zeng,

Roobrouck,

Deschamps

et al. 2024

Blood Advances

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Novel therapies are needed for effective treatment of Acute Myeloid Leukemia (AML). Relapse is common and salvage treatment with cytotoxic chemotherapy is rarely curative. CD123 and CD33, two clinically validated targets in AML, are jointly expressed on blasts and leukemic stem cells in >95% of AML patients. However, their expression is heterogenous between subclones and between patients which may impact the efficacy of single-targeting agents in certain patient populations. We present here a dual- targeting CD33/CD123 NANOBODY® T-cell engager (CD33/CD123-TCE) that was designed to decrease the risk of relapse from possible single antigen-negative clones and to increase coverage within and across patients. CD33/CD123-TCE killed AML tumor cells expressing one or both antigens in vitro. Compared to single-targeting control compounds, CD33/CD123-TCE conferred equal or better ex vivo killing of AML blasts in most primary AML samples tested, suggesting a broader effectiveness across patients. In a disseminated cell line-derived xenograft (CDX) mouse model of AML, CD33/CD123-TCE cleared cancer cells in long bones and in soft tissues. As cytokine release syndrome is a well-documented adverse effect of TCE, the compound was tested in a cytokine release assay and shown to induce less cytokines compared to a CD123 single-targeting control. In an exploratory single-dose non-human primate study, CD33/CD123-TCE revealed a favorable PK profile. Depletion of CD123 and CD33 expressing cells was observed, without signs of cytokine release syndrome nor clinical signs of toxicity. Taken together, the CD33/CD123 dual-targeting NANOBODY® TCE exhibits potent and safe anti-AML activity and promises a broad patient coverage.

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Section: Resultsmentioning

confidence: 99%

“…Antitumor activity was evaluated after MOLM-13-luc AML engraftment in humanized NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ(NSG) mice (Charles River Laboratories, Saint-Germain-Nuelles, France) as described in Bonnevaux et al 37 and Figure 6 A. Whole body and long bones tumor growth was monitored via in-life bioluminescence.…”

Section: Methodsmentioning

confidence: 99%

Dual-targeting CD33/CD123 NANOBODY T-cell engager with potent anti-AML activity and good safety profile

Zeng,

Roobrouck,

Deschamps

et al. 2024

Blood Advances

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“…A clinical trial (NCT02520427) designed to investigate the safety and tolerability of AMG 330 in patients with relapsed/refractory AML is in progress. CD3 − CD123-BiTE antibody is another promising therapy for patients with relapsed/refractory AML ( Bonnevaux et al, 2021 ). Additional early clinical studies are ongoing to investigate CD3 − CD123-BiTE antibodies, such as XmAb14045 (NCT02730312), and flotetuzumab (MGD006; NCT02152956), a dual-affinity retargeting (DART) molecule.…”

Section: Anti-cd3/cd33 or Cd3/cd123 Bispecific Antibodymentioning

confidence: 99%

A perspective of immunotherapy for acute myeloid leukemia: Current advances and challenges

et al. 2023

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During the last decade, the underlying pathogenic mechanisms of acute myeloid leukemia (AML) have been the subject of extensive study which has considerably increased our understanding of the disease. However, both resistance to chemotherapy and disease relapse remain the principal obstacles to successful treatment. Because of acute and chronic undesirable effects frequently associated with conventional cytotoxic chemotherapy, consolidation chemotherapy is not feasible, especially for elderly patients, which has attracted a growing body of research to attempt to tackle this problem. Immunotherapies for acute myeloid leukemia, including immune checkpoint inhibitors, monoclonal antibodies, dendritic cell (DC) vaccines, together with T-cell therapy based on engineered antigen receptor have been developed recently. Our review presents the recent progress in immunotherapy for the treatment of AML and discusses effective therapies that have the most potential and major challenges.

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“…The US FDA approved the CD3/CD19 BsAb‐blinatumomab for the treatment of acute lymphoblastic leukaemia (ALL) in 2014, with 12 BsAbs now in clinical trials in tumour immunotherapy (Table 1), nine BsAbs in pre‐clinical studies (Table 2). Multiple therapeutic targets were identified, including CD47/CD19 [16], CD47/CD20 [17], CD47/GPC3 [18], CD47/PD‐L1 [19], CD3/CD20 [20], NKG2D/2B4 [21], CD3/CD123 [22] and CD28/CLDN18.2 [23]. There are more than 80 types of BsAbs displayed on the China Drug Clinical Trials and Information Disclosure Platform (http://www.chinadrugtrials.org.cn/), and more than 200 types on clinical trial website platform (https://clinicaltrials.gov/).…”

Section: Introductionmentioning

confidence: 99%

“…However, attention is also paid to balancing the relationship between cancer immune response and immunotherapy resistance mechanisms and individualized combination therapy should The US FDA approved the CD3/CD19 BsAbblinatumomab for the treatment of acute lymphoblastic leukaemia (ALL) in 2014, with 12 BsAbs now in clinical trials in tumour immunotherapy (Table 1), nine BsAbs in pre-clinical studies (Table 2). Multiple therapeutic targets were identified, including CD47/CD19 [16], CD47/CD20 [17], CD47/GPC3 [18], CD47/PD-L1 [19], CD3/CD20 [20], NKG2D/2B4 [21], CD3/CD123 [22] and CD28/CLDN18.2 [23]. There are more than 80 types of BsAbs displayed on the China Drug Clinical Trials and Information Disclosure Platform (http://www.…”

Section: Introductionmentioning

confidence: 99%

Advances in the study of CD47‐based bispecific antibody in cancer immunotherapy

Zhang

Fan

et al. 2022

Immunology

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Tumour therapy has entered the era of immunotherapy. Monoclonal antibodies (mAb), immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T), cytokine-induced killer (CIK), tumour-infiltrating lymphocytes (TILs) and other cellular immunotherapies have become the focus of current research. The CD47/ SIRPα target is becoming another popular tumour immunotherapy target following the PDCD1/CD247(PD1/PD-L1) checkpoint inhibitor. In recent years, a large number of CD47/SIRPα mAbs, fusion proteins, and CD47/SIRPα-based bispecific antibodies (BsAbs) are undergoing preclinical and clinical trials and have good curative effects in the treatment of haematological tumours and solid tumours. They bring new vitality and hope for the treatment of patients with advanced tumours. This review summarizes the research progress of CD47/SIRPα-based BsAbs with different targets for tumour treatment. There are 12 and 9 BsAbs in clinical trials and pre-clinical research, respectively. We report on the mechanism of 15 BsAb molecules with different target and analyse the efficacy and safety of preclinical and clinical trials, discuss the issues that may be faced in the development of CD47-based BsAbs, and dual-target molecules, and summarize their development prospects. This review provides a reference for the safety and effectiveness of BsAbs in clinical application and in the future development of antibodies.

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Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment

Cited by 6 publications

References 55 publications

Dual-targeting CD33/CD123 NANOBODY T-cell engager with potent anti-AML activity and good safety profile

Dual-targeting CD33/CD123 NANOBODY T-cell engager with potent anti-AML activity and good safety profile

A perspective of immunotherapy for acute myeloid leukemia: Current advances and challenges

Advances in the study of CD47‐based bispecific antibody in cancer immunotherapy

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