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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 2059: In situ imaging of antibody drug conjugate (ADC) binding and pharmacodynamic biomarkers of response in models of human cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2059-2059
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2059-2059
    Abstract: Antibody drug conjugates (ADCs) are clinically validated as a modality for targeted therapy of solid and hematological cancer due to advancements in target selection, conjugation chemistry and linker technology. However, much about mechanism of action (MoA) is yet to be fully understood. Our goal was to interrogate ADC pharmacokinetics and pharmacodynamics establishing proof of mechanism (PoM) of drug action with a diverse panel of ADCs. Herein, we describe the development of novel immunohistochemical (IHC) methods for in situ visualization of ADCs binding to target expressing cells and their cognate downstream biomarkers of response in formalin fixed paraffin embedded cells/tissues. We demonstrate specific binding of 4 different ADCs spanning 2 solid tumor targets and an endothelial cell target using IHC with anti-human IgG in human tumor xenograft models expressing the respective targets. ADC binding to target is observed as early as 20 minutes after a single dose of ADC at 3 mg/kg. Utilizing an anti-microtubule inhibitor (MTI) payload-specific antibody we additionally detect ADC binding to tumor cells by monitoring the cytotoxic payload. The cell type where the antibodies and payload localized was identified by double and triple IHC. Pharmacodynamic biomarkers of response for two payload classes (DNA damaging agents and MTIs) were detected with antibodies against phospho-Histone H2AX and phospho-Histone H3, respectively - confirming the expected ADC MoAs. Downstream apoptosis of target cells was detected with cleaved caspase 3 IHC. The kinetics of biomarker response and downstream cellular impact was quantified via image analysis with biomarkers evident as early as 24 hours after a single dose for both tumor cell and vascular targets. Furthermore, we observed a correlation between biomarkers of response and efficacy of the ADCs as measured by statistically significant tumor growth inhibition for the 4 ADCs we studied. These data suggest that IHC interrogations of drug action should be used to further the clinical development of ADCs via demonstration of pharmacodynamic activities at the cellular level, establishing PoM data, and enabling predictive preclinical oncology models in order to reduce clinical attrition of ADCs. Citation Format: Jonathon Golas, Andrea T. Hooper, Justin Lucas, Heather Jones, Timothy Nichols, Kiran Khandke, Manoj Charati, Roger Conant, Michael Cinque, Judy Lucas, Marc Damelin, Ken Geles, Caiazzo Teresa, Frank Loganzo, Puja Sapra, Hans-Peter Gerber, Chad May. In situ imaging of antibody drug conjugate (ADC) binding and pharmacodynamic biomarkers of response in models of human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2014-2059
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2059
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract B010: Pharmacodynamics and mechanisms of drug action for bispecific redirected T cell immunotherapy against P-cadherin
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 1_Supplement ( 2016-01-01), p. B010-B010
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 1_Supplement ( 2016-01-01), p. B010-B010
    Abstract: Utilizing pharmacodynamic immunohistochemistry (PD-IHC) for in situ & quantitative measures, we explored the mechanism of action of a Dual-Affinity Re-Targeting (DART®) bispecific recombinant antibody engineered with enhanced pharmacokinetic properties to extend in vivo half-life. This bispecific, designated P-cadherin LP-DART, is designed to engage and activate polyclonal T cell populations via the CD3 complex in the presence of P-cadherin expressing tumors. Following administration in mice bearing established human tumors and implanted with human T-cells we examined the localization of P-cadherin LP-DART within the tumor xenografts, P-cadherin expression, quantitation and immunophenotyping of tumor infiltrating lymphocytes (TILs), downstream biomarkers of T-cell effector function and immunoregulatory mechanisms. Cell surface P-cadherin expression was maintained on the established tumor xenografts after the administration of single and multiple doses of the bispecific molecule. Furthermore, we detected P-cadherin LP-DART in the tumors more than one week after administration. Pan lymphocyte IHC and digital image analysis demonstrated P-cadherin LP-DART mediated CD3+ T-cell infiltration, resulting in nearly half of the viable cells in the tumor being TILs. Conversely, we did not detect infiltrating CD3+ human T-cells in normal organs, confirming a specific target mediated T-cell response at the tumor site. Elevated proximal and downstream mediators of drug action (granzyme B and cleaved caspase 3) further support that P-cadherin LP-DART localized within the tumor induces T-cell mediated growth inhibition and sustained regression. Additionally, to study the the tumor response to redirected T-cell mediated killing we measured the up-regulation of critical immune check point pathways after treatment P-cadherin LP-DART. In the in vivo tumor models examined, tumor cells acutely and robustly induced expression of immunoregulatory pathways in response to effector T-cell activity. Taken together, we demonstrate the utility of in situ kinetic PD-IHC methodologies to demonstrate target expression, drug localization, downstream biomarkers of drug action, and provide insights into potential immunoregulatory mechanisms in response to T-cell mediated bispecific immunotherapy. Citation Format: Justin Lucas, Andrea T. Hooper, Jonathon Golas, Bryan Peano, Alan Opsahl, Leslie Obert, Maria Gavriil, Timothy Fisher, Anton Xavier, Michael Cinque, Roger Conant, Judy Lucas, Adam Root, Lioudmila Tchistiakova, Hans Peter Gerber, Chad May. Pharmacodynamics and mechanisms of drug action for bispecific redirected T cell immunotherapy against P-cadherin. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B010.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-B010
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2732517-9
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  • 3
    Online Resource
    Online Resource
    Beyond Rapalog Therapy: Preclinical Pharmacology and Antitumor Activity of WYE-125132, an ATP-Competitive and Specific Inhibitor of mTORC1 and mTORC2
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 2 ( 2010-01-15), p. 621-631
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 2 ( 2010-01-15), p. 621-631
    Abstract: The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19 ± 0.07 nmol/L; & gt;5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy. Cancer Res; 70(2); 621–31
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-2340
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 4549: Evaluation of GUCY2c-CD3 bispecific targeting GI cancers in an orthotopic colorectal tumor model
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4549-4549
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4549-4549
    Abstract: GUCY2c is a tumor target expressed in & gt;90% of colorectal cancer (CRC). It is also expressed on the apical side of intestinal epithelial tight junctions, where it regulates intestinal fluidity. PF-07062119, a GUCY2c-CD3 bispecific antibody that recruits T cells to GUCY2c expressing gastrointestinal tumors, has shown anti-tumor efficacy in several subcutaneous colorectal cancer models without any signs of intestinal toxicity. Here we describe the effects of PF-07062119 in an intestinal orthotopic xenograft model, created surgically in NSG mice using LS1034 CRC cells expressing luciferase. To establish this model, LS1034-luc tumor fragments were sutured onto the cecum proximal to the colon. Tumor growth was monitored through detection of luciferin bioluminescence. PF-07062119 was administered at 0.03, 0.1 and 0.3 mg/kg iv weekly, along with an adoptive transfer of 2x106 human T cells the day after bispecific compound dosing. At 0.3 mg/kg dose, the bioluminescence signal was significantly reduced compared with the isotype control group. Necropsies at the end of study revealed complete tumor clearance, or residual calcified or fibrotic tissues, at the tumor implant site in all animals of the 0.3 mg/kg group, compared with tumor presence in 9 of 9 animals and liver metastases in 2 of 9 animals in the isotype control group. The average tumor weight of 0.1 mg/kg dose group decreased relative to the control group, but the difference did not reach statistical significance. The results of histological examination indicate enhanced T cell infiltration in the tumor tissues compared with the normal intestinal tissues in PF-07062119 treated animals. No body weight loss or other clinical signs were observed in all groups. These results demonstrate that PF-07062119 can eliminate LS1034 orthotopic tumors and potential metastasis with no observable toxicities. This supports our hypothesis that apical restriction of GUCY2c expression in normal intestine creates tumor-vs-normal differential for selective targeting of GUCY2c positive tumors, and the GUCY2c-CD3 bispecific antibody redirects T cells to lyse the CRC tumor cells. Citation Format: Johnny Yao, Divya Mathur, Sharon Yang, Roger Conant, Jessica Kearney, Vlad Buklan, Jonathan Golas, Edward Rosfjord. Evaluation of GUCY2c-CD3 bispecific targeting GI cancers in an orthotopic colorectal tumor model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4549.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4549
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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