CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy

Willier, Semjon; Rothämel, Paula; Hastreiter, Maximilian; Wilhelm, Jonas; Stenger, Dana; Blaeschke, Franziska; Rohlfs, Meino; Kaeuferle, Theresa; Schmid, Irene; Albert, Michael H.; Binder, Vera; Subklewe, Marion; Klein, Christoph; Feuchtinger, Tobias

doi:10.1182/blood.2020006921

Cited by 59 publications

(59 citation statements)

References 49 publications

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“…approached 95% (14,28,29). A recent analysis documented the high level of expression of CLEC12A and CD33 on patient AML cells as compared to normal cells and noted that these two antigens together are expressed by nearly all pediatric AML (38). Therefore, targeting both CLEC12A and CD33 should be broadly effective in most AML patients.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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Refractory Acute Myeloid Leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies and cellular therapeutics.Here we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers", with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo. This CARengager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.

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Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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“…Additional AML targets that have been investigated for CAR therapies include CD33 [ 35 ], CLEC12A [ 36 ], the high-affinity folate receptor beta [ 37 ], and B7-H3 [ 38 ]. Beyond adoptive cell therapeutic strategies, bi- and tri-specific killer engager (BiKE and TriKE, respectively) approaches appear promising as AML treatment [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123

Morgan

Kloos

Lenz

et al. 2021

Viruses

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Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.

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“…CLEC12A, also known as C-type lectin-like molecule-1 (CLL-1), is a myeloid differentiation antigen expressed by 90–95% of leukemic blasts [ 69 , 70 ]. Additional support for using CLEC12A as an immunotherapy target comes from a recent expression study in pediatric AML patients that showed that the combination of CD33 and CLEC12A was the most frequently upregulated one in pediatric AML samples, making it a potential therapeutic target with limited on-target off-leukemia side effects [ 71 ]. CLEC12A has been evaluated as an immunotherapy target both with antibody-drug conjugates (ADCs) and bispecific antibodies.…”

Section: Antigen Targetsmentioning

confidence: 99%

BiTEs, DARTS, BiKEs and TriKEs—Are Antibody Based Therapies Changing the Future Treatment of AML?

Allen¹,

Zeidan²,

Bewersdorf³

2021

Life

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Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells).

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CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy

Cited by 59 publications

References 49 publications

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123

BiTEs, DARTS, BiKEs and TriKEs—Are Antibody Based Therapies Changing the Future Treatment of AML?

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