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  • 1
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    The human anti-CD40 agonist antibody mitazalimab (ADC-1013; JNJ-64457107) activates antigen-presenting cells, improves expansion of antigen-specific T cells, and enhances anti-tumor efficacy of a model cancer vaccine in vivo
    Springer Science and Business Media LLC ; 2021
    In:  Cancer Immunology, Immunotherapy Vol. 70, No. 12 ( 2021-12), p. 3629-3642
    Details
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 70, No. 12 ( 2021-12), p. 3629-3642
    Abstract: Non-responders to checkpoint inhibitors generally have low tumor T cell infiltration and could benefit from immunotherapy that activates dendritic cells, with priming of tumor-reactive T cells as a result. Such therapies may be augmented by providing tumor antigen in the form of cancer vaccines. Our aim was to study the effects of mitazalimab (ADC-1013; JNJ-64457107), a human anti-CD40 agonist IgG1 antibody, on activation of antigen-presenting cells, and how this influences the priming and anti-tumor potential of antigen-specific T cells, in mice transgenic for human CD40. Mitazalimab activated splenic CD11c + MHCII + dendritic cells and CD19 + MHCII + B cells within 6 h, with a return to baseline within 1 week. This was associated with a dose-dependent release of proinflammatory cytokines in the blood, including IP-10, MIP-1α and TNF-α. Mitazalimab administered at different dose regimens with ovalbumin protein showed that repeated dosing expanded ovalbumin peptide (SIINFEKL)-specific CD8 + T cells and increased the frequency of activated ICOS + T cells and CD44 hi CD62L − effector memory T cells in the spleen. Mitazalimab prolonged survival of mice bearing MB49 bladder carcinoma tumors and increased the frequency of activated granzyme B + CD8 + T cells in the tumor. In the ovalbumin-transfected tumor E.G7-OVA lymphoma, mitazalimab administered with either ovalbumin protein or SIINFEKL peptide prolonged the survival of E.G7-OVA tumor-bearing mice, as prophylactic and therapeutic treatment. Thus, mitazalimab activates antigen-presenting cells, which improves expansion and activation of antigen-specific T cells and enhances the anti-tumor efficacy of a model cancer vaccine.
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    URL: Article
    DOI: 10.1007/s00262-021-02932-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 2
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    751 Neo-X-Prime bispecific antibodies targeting CD40 and tumor antigens promote cross-presentation of tumor exosome-derived neoantigen and induce superior anti-tumor responses compared to CD40 mAb
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A785-A785
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A785-A785
    Abstract: Alligator's Neo-X-Prime platform aims to enable antigen presenting cells to efficiently enhance priming of tumor neoantigen-specific T cells with the goal of overcoming PD-1 resistance in certain tumor types. We hypothesize that binding of a CD40 x TAA bispecific antibody (bsAb) to CD40 on dendritic cells (DCs) and a tumor-associated antigen (TAA) on tumor exosomes or tumor debris leads to (i) activation of the DC, (ii) uptake of the tumor material, (iii) cross-presentation of tumor-derived neoantigen (present in exosomes or debris) and, iv) priming of tumor neoantigen-specific T cells, resulting in an increased quantity and/or quality of the tumor-targeting T cell pool. Methods Functionality was evaluated in vitro using CD40 reporter cells and monocyte-derived DCs, co-cultured with cells expressing TAA. Further, co-localization of TAA-expressing cellular debris with a CD40-expressing human B cell line in the presence of bsAbs was assessed using live cell imaging. In vivo, anti-tumor efficacy and immunological memory were assessed in human CD40 transgenic (hCD40tg) mice bearing MB49 bladder carcinoma tumors transfected with human TAA or controls. T cells isolated from OVA-specific TCR-transgenic mice were used to evaluate the effect of Neo-X-Prime bsAbs on antigen-specific T cell expansion in the presence of hCD40tg DCs and exosomes from MB49 tumors transfected with both human TAA and OVA using flow cytometry. Results Using CEA as a highly expressed TAA, we have developed lead Neo-X-Prime CD40-CEA bsAbs engineered to achieve an optimal profile. Further, using Neo-X-Prime concept molecules targeting EpCAM, we have demonstrated the ability to mediate co-localization of tumor debris and CD40 expressing antigen presenting cells that is dependent on the receptor density of the TAA. We have further shown that addition of Neo-X-Prime bsAbs to a co-culture of murine DCs, T cells and tumor-derived exosomes induces increased expansion of model neoantigen-specific T cells. In vivo, Neo-X-Prime bsAbs display a potent, TAA-dependent anti-tumor effect that is superior to CD40 mAbs. Cured mice develop a broad immunological memory that is not dependent on expression of the TAA. The tumor-localizing property of Neo-X-Prime bsAbs also shows potential for improved safety compared to CD40 monospecific antibodies. Conclusions Neo-X-Prime bsAbs have the potential to tumor-selectively target CD40-expressing antigen-presenting cells to mediate an expansion of the tumor-specific T cell repertoire, resulting in increased T cell infiltration and potent anti-tumor effects. Ethics Approval All experiments were performed after approval from the Malmö/Lund Animal Ethics Committee.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.751
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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  • 3
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    Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 11 ( 2022-11), p. e005018-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 11 ( 2022-11), p. e005018-
    Abstract: Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2022-005018
    Language: English
    Publisher: BMJ
    Publication Date: 2022
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  • 4
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    Abstract 4155: Mitazalimab, a potent CD40 agonist in combination with chemotherapy redirects and activates tumor infiltrating myeloid cells
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 4155-4155
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 4155-4155
    Abstract: Mitazalimab is a human CD40 agonistic antibody developed for immunotherapy of cancer. Activation of CD40, expressed on myeloid cells, such as dendritic cells and tumor infiltrating macrophages, leads to improved T cell priming and initiation of T cell-dependent anti-tumor responses. Mitazalimab is a FcγR crosslinking-dependent IgG1 antibody, with potential for high efficacy and manageable safety profile. Immunologically cold and immune-excluded tumors, such as pancreatic cancer, are defined by low infiltration of immune cells as well as low expression and release of neoantigens. In pancreatic cancer, effector CD8+ T cells are excluded from the tumor by the desmoplastic tumor stroma, which surrounds the tumor and hosts immunosuppressive macrophages that dampen the immune response in the tumor microenvironment. By activating and re-directing tumor infiltrating myeloid cells, CD40 agonists such as mitazalimab, have the potential to augment the response to chemotherapy and spark an effective anti-tumor response by i) priming T cells reactive to the tumor neoantigens released by the chemotherapy, and ii) inducing degradation of the stroma surrounding the tumor thereby enhancing the efficacy of chemotherapy. The ability of mitazalimab to augment the response to chemotherapy was demonstrated in mice, transgenic for human CD40 (hCD40tg), inoculated with the syngeneic tumor cell line MB49. Mitazalimab, administered repeatedly together with FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil and folinic acid), synergized effectively with chemotherapy, inducing long-term survival. The combined treatment improved activation of antigen presenting cells in the circulation, intratumoral T cell responses as well as reduced the amount of intratumoral immunosuppressive M2 macrophages. By converting the MB49 tumor cell line resistant to FOLFIRINOX treatment, we could further demonstrate that the combination of mitazalimab and FOLFIRINOX induced a strong anti-tumor activity also in a chemoresistant variant of the MB49 cell line. In conclusion, mitazalimab synergizes effectively with chemotherapy, leading to induction of long-term survival in a preclinical tumor model by reducing immunosuppressive M2 macrophages and improving T cell responses intratumorally. These preclinical data, together with the clinical data of mitazalimab from the phase 1 study (NCT02829099), where mitazalimab was well tolerated up to 1200 μg/kg with a manageable safety profile, support the ongoing clinical phase 2 study OPTIMIZE-1 (NCT04888312) of mitazalimab in combination with chemotherapy in pancreatic cancer. Citation Format: Karin Enell Smith, Mia Thagesson, Anneli Nilsson, Doreen Werchau, Peter Ellmark. Mitazalimab, a potent CD40 agonist in combination with chemotherapy redirects and activates tumor infiltrating myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4155.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-4155
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    The Bispecific Tumor Antigen-Conditional 4–1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 1 ( 2023-01-03), p. 89-101
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 1 ( 2023-01-03), p. 89-101
    Abstract: 4–1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4–1BB on tumor-specific cytotoxic T cells makes 4–1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4–1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4–1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4–1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4–1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4–1BB–mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-22-0395
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation
    BMJ ; 2019
    In:  Journal for ImmunoTherapy of Cancer Vol. 7, No. 1 ( 2019-12)
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 7, No. 1 ( 2019-12)
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1186/s40425-019-0570-8
    Language: English
    Publisher: BMJ
    Publication Date: 2019
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  • 7
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    Abstract 3623: The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3623-3623
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3623-3623
    Abstract: ATOR-1015 is a CTLA-4 x OX40 bispecific immune activating antibody developed for tumor-directed immunotherapy. ATOR-1015 binds both targets simultaneously, promoting cell-cell interactions expected to enhance the immuno-stimulating effect of the compound. The mode of action of ATOR-1015 is thought to be a combination of regulatory T cell (Treg) depletion and effector T cell activation. It can be seen as a next generation CTLA-4 antibody with tumor-directed activity and augmented Treg depletion. The ability to induce ADCC of human Treg was investigated using an FcγR expressing reporter assay demonstrating superior effect of ATOR-1015 compared to the monospecific antibody counterparts. Further, ATOR-1015 has been shown to induce activation of T cells in the presence of CTLA-4 expressing cells, ability that is not observed when combining the monoclonal counterparts. Syngeneic tumor models in vivo using human transgenic mice cross-reacting with both targets demonstrate that ATOR-1015 reduces tumor growth and prolongs survival. Further, ATOR-1015 treatment demonstrates superior increase in the intratumoral CD8+ T cell/Treg ratio compared to the monospecific counterparts, without affecting systemic T cells. This tumor directed immune activation is demonstrated to be due to the tumor localization abilities of ATOR-1015. In conclusion, ATOR-1015 is a next generation CTLA-4 antibody with tumor directed activity with augmented T-reg depletion. It is currently in GLP manufacturing of clinical material and will start clinical trials in the second half of 2018. Citation Format: Niina Veitonmäki, Mia Thagesson, Doreen Werchau, Karin Hägerbrand, Kristine Smedenfors, Anne Månsson-Kvarnhammar, Anna Rosén, Maria Johansson, Christina Furebring, Per Norlén, Peter Ellmark. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3623.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3623
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Abstract 695: The generation of a mono-selective CDK7 inhibitor.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 695-695
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 695-695
    Abstract: Cyclin-depending kinase (CDK) family members that trigger passage through the cell cycle have been considered as attractive cancer targets for at least two decdes Yet, the first generation of pan-specific CDK inhibitors failed to show clinical efficacy due to their small therapeutic window. CDK family members that control processes such as transcription have caught less attention, although experimental evidence for an involvement in different pathological processes is emerging. CDK7 (or CAK) has essential roles in both the cell-division cycle and transcription, and serves as a direct link between the regulation of basal transcription and the cell cycle. In addition to its role as a transcription activator, CDK7 has been reported to act on specific transcription events by phosphorylating a series of specific transcription factors, such as the estrogen receptor and p53. These findings indicate that CDK7 is a potential target for cancer therapy, and perhaps inflammation. The detailed molecular characterization of the biological role of CDK7, as well as its therapeutic validation, is dependent on the development of highly specific and potent CDK7 inhibitors. We have developed a series of CDK7 inhibitors with picomolar potency on CDK7, more than 1000-fold selectivity over any other CDK, and single digit nM inhibition of sensitive cancer cell lines. Interestingly, a broad screen of & gt;200 different tumor cell lines lead to the identification of responder and non-responder cell lines. Non-responder tumor lines, similar to primary cells are at least by a factor of 1000 less sensitive to the inhibition with the mono-selective CDK7 inhibitor. Our findings further indicate that CDK7 is neither essential for general transcription, nor for the progression through the cell cycle. It rather coordinates cell line specific biological processes. The effects of selective CDK7 inhibitors on tumor cell lines are clearly distinct from existing, nonselective pan-CDK inhibitors. The responder status for a subset of cancer cell lines can be predicted with a distinct biomarker. Chemical optimization of the selective inhibitor lead to a compound which shows dose-dependent pharmacological efficacy in mouse xenograft models after oral administration, with no signs of toxicity at the efficacious doses. Citation Format: Jan E. Eickhoff, Gunther Zischinsky, Axel Choidas, Peter Habenberger, Alexander Wolf, Carsten Degenhardt, Matthias Baumann, Anke Unger, Ahmad Ghallab, Doreen Werchau, Jan Hengstler, Peter Nussbaumer, Bert M. Klebl. The generation of a mono-selective CDK7 inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 695. doi:10.1158/1538-7445.AM2013-695
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-695
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    Abstract 2380: Preclinical safety and efficacy of a tumor-directed T cell activating 4-1BB x 5T4 ADAPTIR™ bispecific antibody
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2380-2380
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2380-2380
    Abstract: The ability to induce potent anti-tumor activity by stimulating 4-1BB (CD137), a key co-stimulatory receptor, makes 4-1BB an attractive immunotherapeutic target. However, a clinically tested, 4-1BB targeting monospecific antibody has been hampered by dose-limiting hepatic toxicities. To improve safety of 4-1BB targeting therapies we have developed a 4-1BB x 5T4 bispecific antibody designed to direct tumor-specific T cell responses to the tumor by stimulating 4-1BB only when co-engaged with 5T4, a tumor-associated antigen. The preclinical dataset presented here provides an overview of the mechanism of action and the efficacy and safety profile of ALG.APV-527, supporting its advancement into the clinic. ALG.APV-527 was built using the ADAPTIR™ platform with binding domains from the ALLIGATOR-GOLD® human scFv library. Its 5T4-dependent agonistic function was assessed using primary CD8+ T cells or NK cells in the presence of 5T4-expressing cells. Secretion of IFN-γ or granzyme B was measured at 72 hrs using ELISA. To measure proliferation, PBMCs were labelled with Cell Trace™ and gated CD8+ T cells were analyzed using flow cytometry. For tumor inhibition studies, the human 5T4-expressing colon carcinoma HCT116 xenograft model was used. 5T4 expression was evaluated in normal human tissues and different human tumors by immunohistochemistry. The preclinical safety profile of ALG.APV-527 was evaluated in a single and repeated dose, dose-range finding toxicology study in non-human primates (NHP). The study design included all the standard repeated dose toxicity parameters and in addition, pharmacokinetics, immunogenicity, and pharmacodynamic end-points. ALG.APV-527 induces a 5T4-dependent increase in IFN-γ and granzyme B production and enhances proliferation of T cells and NK cells. Furthermore, ALG.APV-527 inhibits tumor growth in a human 5T4-expressing colon carcinoma xenograft model. 5T4 is overexpressed in multiple solid tumors, potentially directing the activity of 4-1BB induced by ALG.APV-527 to 5T4-expressing tumors, improving the risk/benefit profile. Four doses (administered once weekly) did not cause any adverse events in the NHP toxicity study. In conclusion, ALG.APV-527 induces potent CD8+ T cell and NK co-stimulation but only in the presence of 5T4. Based on its efficacy and preclinical safety profile, ALG.APV-527 is a promising anti-cancer therapeutic for the treatment of multiple 5T4-expressing solid tumors. Citation Format: Anna Dahlman, Michelle Nelson, Jeannette Bannink, Starrla Johnson, Doreen Werchau, Anneli Nilsson, Lill Ljung, Gabriele Blahnik-Fagan, Robert Bader, Adnan Deronic, Peter Ellmark, Maria Askmyr, Gabriela Hernandez-Hoyos, Cathy McMahan, Sara Fritzell. Preclinical safety and efficacy of a tumor-directed T cell activating 4-1BB x 5T4 ADAPTIR™ bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2380.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2380
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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