In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Michalska, Marta; Schultze-Seemann, Susanne; Kuckuck, Irina; Wolf, Philipp

doi:10.21873/anticanres.12192

Cited by 7 publications

(10 citation statements)

References 32 publications

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“…With hD7-1(VL-VH)-PE24 IC 50 values of 82 pM and 24 pM on LNCaP and C4-2 cells, respectively, were reached after 72 h incubation. For hD7-1(VL-VH)-PE40 similar IC 50 values of 25 pM and 6 pM were determined [44]. This example proves that size reduction of a toxin domain can be done without or only marginally impairment of cytotoxicity.…”

Section: Enhancing Tumor Penetration and Affinitysupporting

confidence: 59%

“…It is important that the specific antigen binding is not lost during the humanization process and that the cytotoxicity of targeted toxins, into which the humanized antibody or antibody fragments are incorporated, is still sufficient. In studies with PE-based targeted toxins containing murine or humanized anti-PSMA scFv as binding domains, specific binding to PSMA expressing LNCaP and C4-2 cells with comparable binding constants and cytotoxicity for both variants were described [18,44,46].…”

Section: Solutions For Reduction Of Immunogenicity 621 Reducing the Immunogenicity Of The Binding Domainmentioning

confidence: 99%

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Targeted Toxins for the Treatment of Prostate Cancer

Wolf

2021

Biomedicines

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Prostate cancer is the second most common cancer and the fifth leading cause of cancer deaths worldwide. Despite improvements in diagnosis and treatment, new treatment options are urgently needed for advanced stages of the disease. Targeted toxins are chemical conjugates or fully recombinant proteins consisting of a binding domain directed against a target antigen on the surface of cancer cells and a toxin domain, which is transported into the cell for the induction of apoptosis. In the last decades, targeted toxins against prostate cancer have been developed. Several challenges, however, became apparent that prevented their direct clinical use. They comprise immunogenicity, low target antigen binding, endosomal entrapment, and lysosomal/proteasomal degradation of the targeted toxins. Moreover, their efficacy is impaired by prostate tumors, which are marked by a dense microenvironment, low target antigen expression, and apoptosis resistance. In this review, current findings in the development of targeted toxins against prostate cancer in view of effective targeting, reduction of immunogenicity, improvement of intracellular trafficking, and overcoming apoptosis resistance are discussed. There are promising approaches that should lead to the clinical use of targeted toxins as therapeutic alternatives for advanced prostate cancer in the future.

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Section: Enhancing Tumor Penetration and Affinitysupporting

confidence: 59%

Section: Solutions For Reduction Of Immunogenicity 621 Reducing the Immunogenicity Of The Binding Domainmentioning

confidence: 99%

Targeted Toxins for the Treatment of Prostate Cancer

Wolf

2021

Biomedicines

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“…Second, besides silencing TRIM24 expression in CRPC, PSMAb containing the constant region of human IgG1 induced additional therapeutic effects of ADCC and CDC. The vast majority of targeted therapy for CRPC, on the other hand, used receptor ligands, peptides, or scFv that could only identify and bind with antigens and lacked additional therapeutic effects 36, 37. Third, PSMAb-based TRIM24 siRNA delivery had high affinity with PSMA, which is approximately ten times higher than that of the extensively studied J591 PSMA antibody (3 nM) 38, and was helpful in avoiding the off-target effects during therapy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

Shi¹,

Wang²,

Han³

et al. 2019

Theranostics

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Background and Aims : Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro . Methods : The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo . CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro , whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results : We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo . Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro , and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo . Conclusion : PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.

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“…Epitope de-immunization strategies have shown promise in reducing the immunogenicity of other sequence-modified proteins including recombinant immunotoxins used for cancer therapies [65,66,67,68,69,70,71,72], interferon-β [73], interferon-α [72], staphylokinase [74], β-lactamase [75], Epo [33,37], and monoclonal antibodies [37,76]. Admittedly, some immunodominant epitopes will correspond to sequences that cannot be altered without impacting functionality of the biotherapeutic, and the major impact of epitope mapping may eventually be to facilitate novel approaches to tolerize patients to specific antigens [77,78,79].…”

Section: Identifying and Modifying Hla-restricted T-cell Epitopes mentioning

confidence: 99%

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

Pratt

2018

Antibodies

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Abstract:The development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in some cases even reverse such deleterious immune responses. CD4 + T cells are essential players in the development of most ADAs, while memory B-cell and long-lived plasma cells amplify and maintain these responses. This review summarizes methods to predict and experimentally identify T-cell and B-cell epitopes in therapeutic proteins, with a particular focus on blood coagulation factor VIII (FVIII), whose immunogenicity is clinically significant and is the subject of intensive current research. Methods to phenotype ADA responses in humans are described, including T-cell stimulation assays, and both established and novel approaches to determine the titers, epitopes and isotypes of the ADAs themselves. Although rational protein engineering can reduce the immunogenicity of many biotherapeutics, complementary, novel approaches to induce specific tolerance, especially during initial exposures, are expected to play significant roles in future efforts to reduce or reverse these unwanted immune responses.

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In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Cited by 7 publications

References 32 publications

Targeted Toxins for the Treatment of Prostate Cancer

Targeted Toxins for the Treatment of Prostate Cancer

Therapeutic effects of human monoclonal PSMA antibody-mediated TRIM24 siRNA delivery in PSMA-positive castration-resistant prostate cancer

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

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