Development of a novel fully-human anti-CD123 antibody to target acute myeloid leukemia

Hutmacher, Cornelia; Volta, Laura; Rinaldi, Francesco; Murer, Patrizia; Myburgh, Renier; Manz, Markus G.; Neri, Dario

doi:10.1016/j.leukres.2019.106178

Cited by 19 publications

(13 citation statements)

References 46 publications

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“…This could be due to a steric hindrance of functional immunological synapse formation by trimeric 4–1BBL, as the fusion of 4–1BBL already lead to a comparably lower target binding affinity as well as a reduced accessibility of TM123-4-1BBL´s UCE-tag. Nevertheless, in comparison with alternative constructs that address CD123 as a target structure such as flotetuzumab (MGD006), 61 two novel CD123xCD3 Bispecific T cell Engager (BiTE) 62 and APVO436, 63 TM123-4-1BBL-redirected UniCAR-T still displayed comparable in vitro efficacy in the picomolar range. In addition to target cell lysis, EC 50 values for cytokine secretion of IL-2, IFN-γ and GM-CSF revealed higher TM123-4-1BBL doses for reaching half-maximal cytokine secretion levels compared to attaining half-maximal lysis.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

et al. 2021

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Chimeric antigen receptor T cells (CAR-T) targeting CD19 have achieved significant success in patients with B cell malignancies. To date, implementation of CAR-T in other indications remains challenging due to the lack of truly tumor-specific antigens as well as control of CAR-T activity in patients. CD123 is highly expressed in acute myeloid leukemia (AML) blasts including leukemia-initiating cells making it an attractive immunotherapeutic target. However, CD123 expression in normal hematopoietic progenitor cells and endothelia bears the risk of severe toxicities and may limit CAR-T applications lacking fine-tuned control mechanisms. Therefore, we recently developed a rapidly switchable universal CAR-T platform (UniCAR), in which CAR-T activity depends on the presence of a soluble adapter called targeting module (TM), and confirmed clinical proof-of-concept for targeting CD123 in AML with improved safety. As costimulation via 4-1BB ligand (4-1BBL) can enhance CAR-T expansion, persistence, and effector functions, a novel CD123-specific TM variant (TM123-4-1BBL) comprising trimeric single-chain 4-1BBL was developed for transient costimulation of UniCAR-T cells (UniCAR-T) at the leukemic site in trans. TM123-4-1BBL-directed UniCAR-T efficiently eradicated CD123-positive AML cells in vitro and in a CDX in vivo model. Moreover, additional costimulation via TM123-4-1BBL enabled enhanced expansion and persistence with a modulated UniCAR-T phenotype. In addition, the increased hydrodynamic volume of TM123-4-1BBL prolonged terminal plasma half-life and ensured a high total drug exposure in vivo. In conclusion, expanding the soluble adapter optionality for CD123-directed UniCAR-T maintains the platforms high anti-leukemic efficacy and immediate control mechanism for a flexible, safe, and individualized CAR-T therapy of AML patients.

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Section: Discussionmentioning

confidence: 99%

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

et al. 2021

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“…However, healthy hematopoietic cells also express this marker, therefore decreasing this strategy's specificity [120][121][122][123][124]. Ongoing clinical trials are investigating other cell surface targets such as CD47, CD123 and CLL-1, which may improve LSCs targeting; leading to better clinical outcomes in AML patients [125][126][127].…”

Section: Therapeutic Limitations Of Descriptive Genomics In Amlmentioning

confidence: 99%

Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure

Pasquer

Tostain

Kaci

et al. 2021

Cancers

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Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients’ overall survival. The more recent development of functional genomic studies, pushed by novel molecular biology technologies (short hairpin RNA (shRNA) and CRISPR-Cas9) and bioinformatics tools design on one hand, along with the engineering of humanized physiologically relevant animal models on the other hand, have opened a new genomics era resulting in a greater knowledge of AML physiopathology. Combining descriptive and functional genomics will undoubtedly open the road for an AML cure within the next decades.

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“…There were 13/42 responders (6 stringent complete responses (sCRs), 3 complete responses (CRs), 2 very good partial responses (VGPRs), and 2 partial responses (PRs)) [72]. A number of BiTEs targeting CD33, CD123, and CLEC12A/CCL-1 (CD371) have been developed for AML [73][74][75][76]. The full-length human IgG1 bispecific antibody MCLA-117 targeting CLEC12AxCD3 is also currently being tested in AML (NCR03038230) [77].…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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Development of a novel fully-human anti-CD123 antibody to target acute myeloid leukemia

Cited by 19 publications

References 46 publications

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

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