Elimination of different leukaemia subtypes using novel <scp>CD</scp>89‐specific human cytolytic fusion proteins

Gresch, Gerrit; Schenke, Lea; Mladenov, Radoslav; Zwirner, S.; Cremer, Christian; Niesen, Judith; Grieger, Elena; Brümmendorf, Tim H.; Jost, Edgar; Fischer, Rainer; Stockmeyer, Bernhard; Barth, Stefan; Nachreiner, Thomas; Stein, Christoph

doi:10.1111/bjh.14971

Cited by 7 publications

(7 citation statements)

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“…The same study showed the ability of the human cytolytic fusion protein to kill leukemic cells independently of the target receptor profile, which suggests the high potency of MAP tau as cytostatic agent [ 64 ]. In the context of leukaemia, similar results on the efficacy of MAP tau were obtained when evaluating CD89 as a target for immunotherapy [ 69 ]. Taken together, these findings confirm the versatility and the therapeutic suitability of MAP-based immunotherapeutic agents for the treatment of a wide range of indications, including immunological diseases.…”

Section: Microtubule Associated Protein (Map) Tau: Discovery and Smentioning

confidence: 60%

Human MAP Tau Based Targeted Cytolytic Fusion Proteins

et al. 2017

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Some of the most promising small molecule toxins used to generate antibody drug conjugates (ADCs) include anti-mitotic agents (e.g., auristatin and its derivatives) which are designed to attack cancerous cells at their most vulnerable state during mitosis. We were interested in identifying a human cystostatic protein eventually showing comparable activities and allowing the generation of corresponding targeted fully human cytolytic fusion proteins. Recently, we identified the human microtubule associated protein tau (MAP tau), which binds specifically to tubulin and modulates the stability of microtubules, thereby blocking mitosis and presumably vesicular transport. By binding and stabilizing polymerized microtubule filaments, MAP tau-based fusion proteins skew microtubule dynamics towards cell cycle arrest and apoptosis. This biological activity makes rapidly proliferating cells (e.g., cancer and inflammatory cells) an excellent target for MAP tau-based targeted treatments. Their superior selectivity for proliferating cells confers additional selectivity towards upregulated tumor-associated antigens at their surface, thereby preventing off-target related toxicity against normal cells bearing tumor-associated antigens at physiologically normal to low levels. In this review, we highlight recent findings on MAP tau-based targeted cytolytic fusion proteins reported in preclinical immunotherapeutic studies.

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Section: Microtubule Associated Protein (Map) Tau: Discovery and Smentioning

confidence: 60%

Human MAP Tau Based Targeted Cytolytic Fusion Proteins

et al. 2017

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“…Unfortunately, Ang therapeutic efficacy has been hampered by the antagonistic effect of the endogenous human placental ribonuclease inhibitor 1 (RNH1), which acts to prevent self-tissue damage [34,212,225,226]. To bypass this obstacle, Cremer et al (2015) and Gresch et al (2018), engineered multiple Ang mutant versions, which have decreased affinity for their RNH1 [34,223]. According to these studies, the Ang mutants were associated with increased cytotoxicity towards CD64 (activated macrophages) and CD89 positive cells (acute myeloid leukaemia) compared with their wild-type and the gold standard ETA'-hCFP, respectively [34,223,227].…”

Section: Angiogeninmentioning

confidence: 99%

“…To bypass this obstacle, Cremer et al (2015) and Gresch et al (2018), engineered multiple Ang mutant versions, which have decreased affinity for their RNH1 [34,223]. According to these studies, the Ang mutants were associated with increased cytotoxicity towards CD64 (activated macrophages) and CD89 positive cells (acute myeloid leukaemia) compared with their wild-type and the gold standard ETA'-hCFP, respectively [34,223,227]. Their targeted cytotoxic effects were corroborated by Yoon et al (1999) which specifically killed EGFR-expressing cells using EGFR-Ang fusion proteins using IC 50 concentrations of 12.5-45 nM [223,227].…”

Section: Angiogeninmentioning

confidence: 99%

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Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies

et al. 2020

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The epidermal growth factor receptor (EGFR) has been recognized as an important therapeutic target in oncology. It is commonly overexpressed in a variety of solid tumors and is critically involved in cell survival, proliferation, metastasis, and angiogenesis. This multi-dimensional role of EGFR in the progression and aggressiveness of cancer, has evolved from conventional to more targeted therapeutic approaches. With the advent of hybridoma technology and phage display techniques, the first anti-EGFR monoclonal antibodies (mAbs) (Cetuximab and Panitumumab) were developed. Due to major limitations including host immune reactions and poor tumor penetration, these antibodies were modified and used as guiding mechanisms for the specific delivery of readily available chemotherapeutic agents or plants/bacterial toxins, giving rise to antibody-drug conjugates (ADCs) and immunotoxins (ITs), respectively. Continued refinement of ITs led to deimmunization strategies based on depletion of B and T-cell epitopes or substitution of non-human toxins leading to a growing repertoire of human enzymes capable of inducing cell death. Similarly, the modification of classical ADCs has resulted in the first, fully recombinant versions. In this review, we discuss significant advancements in EGFR-targeting immunoconjugates, including ITs and recombinant photoactivable ADCs, which serve as a blueprint for further developments in the evolving domain of cancer immunotherapy.

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“…This construct was easily purified to homogeneity and seemed to retain full ribonucleolytic activity. Most recently, Gresch et al [ 83 ] have demonstrated the significant increase in the pro-apoptotic efficacy of an anti-CD89 (scFv)- AngGGRR in AML-derived target cells and leukemic blasts, compared to the conventional IT, ETA. Table 2 comprises more examples of RNase-based fusions and immunoRNases.…”

Section: Rnases Studied For Cytotoxicity and Anti-cancer Activitymentioning

confidence: 99%

Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

et al. 2018

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Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell’s metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents.

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Elimination of different leukaemia subtypes using novel CD89‐specific human cytolytic fusion proteins

Cited by 7 publications

References 9 publications

Human MAP Tau Based Targeted Cytolytic Fusion Proteins

Human MAP Tau Based Targeted Cytolytic Fusion Proteins

Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies

Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

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