Paul Moore Research Articles

Assessment symposium assessment practice in a changing world

The University English Centres of Australia (UECA) 'Assessment Symposium: Assessment Practice in a Changing World' at Southern Cross University in October 2022 highlighted the growing interest in integrated assessment in Australian university direct entry programs (DEPs) for English as Additional Language (EAL) students. In keynote presentations, Professor Antony John Kunnan, Carnegie Mellon University; Professor Guoxing Yu, University of Bristol; and Dr Paul Moore, the University of Queensland, shared an overview of their scholarly work on integrated assessment. The Symposium also included practitioner and student voices from Australia’s English language intensive courses for overseas students (ELICOS) sector in a panel discussion that considered the impacts of integrated and online assessment on assessment practices in their contexts over the previous three years. This paper provides excerpts from these speakers, contextualised with a brief discussion of DEPs globally, and focussing on the Australian university DEP context.

Abstract 1555: Enhanced HER2-dependent immune activation by margetuximab, an investigational Fc-engineered anti-HER2 mAb, supports combination with checkpoint blockade

Abstract Background: Margetuximab (M) has demonstrated anti-tumor activity in patients with advanced HER2+ gastric cancer and PFS superiority to trastuzumab (T) in pre-treated metastatic HER2+ breast cancer patients (1). Similar to T, M inhibits HER2 signaling; additionally, M enhances engagement with the activating Fcγ receptor (FcR)IIIA, while diminishing interaction with the inhibitory FcRIIB. Given the role of FcRs in coupling innate and adaptive immune responses, clinical studies of M in combination with PD-1 or PD-1 plus LAG-3 blockade have been initiated (2,3). The combination of M with tebotelimab, an investigational bispecific DART® molecule blocking PD-1 and LAG-3, has demonstrated encouraging early evidence of anti-tumor activity in patients with advanced HER2+ malignancies, including those with PD-L1-negative tumors (3). Here we present data supporting the potential mechanisms underlying the anti-tumor activity elicited by M and tebotelimab combination therapy. Methods: PBMCs were challenged with HER2-expressing tumor cell lines in the presence of M or T. Immune modulation was assessed by analysis of immune cell phenotype, gene expression profiles, and cytokine secretome. Functional activity of immune cells following exposure to the combination of M with tebotelimab was evaluated. Results: M induced greater upregulation relative to T of both co-stimulatory (eg 4-1BB) and/or checkpoint molecules (eg PD-L1 and LAG-3) on NK cells and/or monocytes in PBMCs cocultured with HER2-expressing tumor cells. Compared with T, M also induced greater proinflammatory cytokine release, including IFNγ that in turn upregulates PD-L1 and MHC class I expression on co-cultured tumor cells. These effects were not observed with an Fc-null version of M or were inhibited by the addition of FcR-blocking Abs, demonstrating Fc:FcR dependency of M-induced immune activation. Interestingly, CD8 T cells, which lack FcR, also exhibited LAG-3 upregulation in the above cultures, suggesting the effects of M can also be mediated via a cascade mechanism. An IFNγ neutralizing mAb reduced tumor cell-associated PD-L1 and MHC class I upregulation, but not LAG-3 induction on T-cells. PBMCs, pre-treated with a combination of M and tebotelimab in the presence of HER2-expressing tumor cells, demonstrated enhanced cytolytic activity against both the canonical NK cell target, K562, or M-opsonized HER2-positive tumor cells. Conclusions: M, through an Fc-dependent mechanism, can upregulate checkpoint molecules on NK-cells, CD8 T cells and tumor cells, thereby sensitizing them to immune checkpoint blockade. In turn, PD-1 and LAG-3 blockade by tebotelimab enhances M-mediated NK cell cytolytic activity in vitro.

Paul Moore's Centennial Land Run Monument

In 2019, Sculptor Paul Moore FNSS completed his monument of the 1889 Centennial Land Run in Oklahoma City, OK. It took him over twenty years to complete this powerful work, which is one of the largest monuments in the world. It stretches over an area slightly larger than a football field and contains forty‐five powerful sculptures of horsemen and wagons racing over the Oklahoma landscape of hills and creek. It is a vision that caught the moment after a cannon announced the beginning of the Land Run, in which over 50,000 individuals took part in an effort to claim land in the Oklahoma Territory. The sculpture contains masterful images of straining horses and frantic individuals caught in a vital effort to succeed in this race to claim valuable homesteads and pastureland. Moore was awarded the Medal of Honor by the National Sculpture Society this past October, partially in regard for this outstanding public work and the quality of sculpture this extraordinarily talented artist has created in his lifetime.

In Memoriam: Paul Brian Moore (1940–2019)

Paul Moore died on 2 March 2019 in Houston, Texas, and Science lost the greatest mineralogist of the twentieth century. He was equally adept at both classical and modern techniques and excelled at ...

Abstract 1538: Margetuximab mediates greater Fc-dependent anti-tumor activities than trastuzumab or pertuzumab in vitro

Abstract Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody (mAb) with potential for greater immune-mediated anti-tumor activity than trastuzumab (T). M and T bind the same subdomain IV epitope, but M binds with higher affinity to activating Fc receptor, CD16A (FcγRIIIA), and lower affinity to inhibitory Fc receptor, CD32B (FcγRIIB). Pertuzumab (P) binds to a subdomain II epitope and has the same wild type Fc domain as T. We compared in vitro properties of M, T and P and combinations of M+P and T+P to evaluate Fc domain contributions to anti-HER2 mAb mediated activities. By surface plasmon resonance, M, T and P bound to the HER2 extracellular domain with similar high affinity. Binding affinities of M and T were unchanged if P was pre-bound, indicating lack of interaction. M, T and P exhibited comparable binding to HER2-expressing cell lines. Anti-proliferative activities of M and T toward HER23+ cells (N87, SKBR3 or BT474) in the absence or presence of ligands (EGF or HRG1β) were similar, whereas P exhibited weaker activity. In the absence of ligands, M+P or T+P were comparably as active as M or T alone. In presence of ligands, M+P and T+P were generally more active than M or T alone. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated with N87 and SKBR3 target cells (HER23+, expressing a reporter gene to measure viability) and NK effector cells from donors with differing CD16A158 genotypes. M was 7- to 84-fold more potent than T, as well as 69- to 744-fold more potent than P. Greater differences generally were seen with effector NK cells bearing the more common CD16A158 FF and VF genotypes than with the less common, high affinity CD16A158 VV genotype. While addition of P enhanced mean potency of T by 2- to 3-fold, no such effect was seen with M; however, M or M+P was 7- to 25-fold more potent than T+P. Results with JIMT-1 cells (HER22+) were similar, albeit with lower differential than with HER23+ target cells. NK cells were monitored by flow cytometry following incubation of peripheral blood mononuclear cells with HER2+ target cells and mAbs. M induced greater expression of markers of activation (CD137), cytolytic capability (granzyme B, perforin) and proliferation (Ki67) than T. An anti-HER2 mAb with an inactivated Fc domain was ineffective, indicating that induced changes in NK cells were Fc-dependent. In conclusion, M and T bind HER2 with similar affinity and exhibit comparable anti-proliferative activity that is enhanced by addition of P if ligands (EGF or HRG1β) are present. Relative to T, M mediates superior ADCC with effector cells of all CD16A genotypes and promotes greater NK cell activation and expansion. The M+P combination maintains superior ADCC compared to the T+P combination. Citation Format: Liqin Liu, Yinhua Yang, Robert Burns, Jonathan Li, Haiquan Li, Sergey Gorlatov, Paul Moore, Jeffrey Nordstrom. Margetuximab mediates greater Fc-dependent anti-tumor activities than trastuzumab or pertuzumab in vitro [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 1538.

Abstract CT085: Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody

Abstract Background: The role of the PD-1 / PD-L1 axis in limiting T cell activity has been well established. Effective blockade of this pathway has been demonstrated to lead to an increase in T cell activity and to yield clinical activity in cancer patients. INCMGA00012 is a humanized IgG4 monoclonal antibody that binds to human PD-1 and blocks its interaction with PD-L1/PD-L2. This therapeutic antibody has demonstrated acceptable tolerability with evidence of clinical activity in a phase 1 study in patients with solid tumors (NCT03059823). Pharmacodynamic markers demonstrating biological activity of INCMGA0012 were assessed in samples collected during the study. Methods: Blood samples were collected at baseline and at various time points following treatment from patients receiving doses of either 3mg/Kg (Q2W) in the tumor-specific expansion cohort or a flat-dose of 500 or 750mg (Q4W) in the tumor-agnostic expansion cohort. Receptor occupancy was measured on circulating T cells by flow cytometry and serum cytokine levels were measured using either a proximity extension assay or immunoassays. In addition, circulating immune cell phenotyping was analyzed using flow cytometry and PBMC functionality evaluated using ex-vivo re-stimulation. Results: All tested doses of INCMGA0012 evaluated demonstrated a full saturation of the PD-1 receptor at trough on circulating CD4 and CD8 T cells. In all tested cohorts, an increase in serum CXCL9 and CXCL10 was observed following infusion with INCMGA0012. Moreover, an increase in the proliferation of circulating T cells was observed on treatment compared to baseline. Concurrently, following ex vivo re-stimulation, T cells isolated from peripheral blood mononuclear cells demonstrated an increased capacity to secrete cytokines. Conclusion: These results provide evidence that INCMGA0012 is biologically active and leads to an increase in IFNγ-related protein levels (i.e. CXCL9 and CXCL10) and in T cell proliferation. The clinical activity of INCMGA0012 is undergoing further evaluation in several indications, including endometrial cancer, Merkel cell carcinoma and squamous carcinoma of the anal canal. Several combination studies have also been initiated. Citation Format: Thomas Condamine, Sherry Owens, Patricia Feldman, Ross La Motte-Mohs, John Muth, Bradley Sumrow, Paul Moore, Robert Newton. Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal 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 CT085.

Abstract 1533: IMGC936, a first-in-class ADAM9-targeting antibody-drug conjugate, demonstrates promising anti-tumor activity

Abstract Dysregulation of ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family of proteases, has been implicated in tumor progression and metastasis, as well as pathological neovascularization. ADAM9 overexpression correlates with poor prognosis in multiple cancers. We have shown that ADAM9 is overexpressed in multiple solid tumor indications and that anti-ADAM9 antibodies are efficiently internalized and degraded by tumor cell lines making ADAM9 an attractive target for antibody-drug conjugate (ADC) development. Here, we describe IMGC936, the first ADAM9-targeting ADC to enter preclinical development. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable peptide linker at a drug-antibody ratio of two. To maximize the potential for IMGC936 activity, the M252Y/S254T/T256E (YTE) mutation was introduced into the CH2 domain of the antibody to increase in vivo plasma half-life and exposure. In vitro studies demonstrated targeted cytotoxicity of IMGC936 across a panel of ADAM9-positve tumor cell lines with activity at least 2 logs greater than a non-targeting conjugate. Consistent with the in vitroactivity, an anti-ADAM9-DM21 conjugate displayed compelling anti-tumor activity in multiple xenograft models representing non-small cell lung, gastric and colorectal cancers. For example, in the EBC-1 non-small cell lung cancer subcutaneous xenograft model with only moderate ADAM9 expression (H-score of 130), anti-ADAM9-DM21 not only induced tumor growth delay but produced complete and durable remissions in 6/6 mice following a single intravenous dose of 8.6 mg Ab/kg (100 ug DM21/kg). IMGC936 demonstrated a favorable pharmacokinetic profile with good conjugate stability in non-human primates. Importantly, IMGC936 was well-tolerated following repeat dosing in cynomolgus monkeys with no ADAM9 target-related toxicities identified at doses exceeding the levels required for anti-tumor activity in murine xenograft models. Based on the totality of the preclinical data, IMGC936 represents a promising therapeutic candidate to target a wide range of ADAM9-expressing tumors. Citation Format: Stuart Hicks, Deryk Loo, Kerstin Sinkevicius, Juniper Scribner, Bhaswati Barat, Nicholas Yoder, Christopher Espelin, Marian Themeles, Francine Chen, Jacquelynn Lucas, Jennifer Brown, Bahar Matin, Megan Fuller, Jenny Lee, Paulin Salomon, Juliet Costoplus, Sadiqa Yancey, Gundo Diedrich, Sergey Gorlatov, Thomas Son, Michael Chiechi, Pam Li, Michael Spliedt, Valentina Ciccarone, Jeff Hooley, Nadia Gantt, James Tamura, Kerry Donahue, Paul Moore, Syd Johnson, Thomas Chittenden, Richard Gregory, Ezio Bonvini. IMGC936, a first-in-class ADAM9-targeting antibody-drug conjugate, demonstrates promising anti-tumor activity [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 1533.

Abstract 554: Tumor-antigen 5T4-dependent activation of the CD137 costimulatory pathway by bispecific 5T4 x CD137 x CD137 TRIDENT™ molecules

Abstract Introduction: Trophoblast glycoprotein 5T4 is expressed on the cell surface of multiple cancers yet sparingly on normal adult tissues. CD137 (4-1BB) is a co-stimulatory molecule expressed by activated T and NK cells that support cell activation, proliferation and survival. Previously we described bispecific tumor associated antigen x CD137 DART® molecules limiting CD137 mediated immunostimulation to the tumor microenvironment (AACR2017) as an approach to reduce the unwanted systemic CD137 effects associated with agonistic anti-CD137 mAbs. We subsequently identified a bispecific TRIDENT format bearing bivalent CD137 and monovalent tumor antigen engagement that provides maximal CD137 activation in a tumor antigen anchored manner. Here we apply that format to generate a 5T4 x CD137 x CD137 TRIDENT molecule that promotes CD137 activation in proximity to 5T4-expressing tumor cells leading to enhanced T-cell co-stimulation, proliferation and tumor cell killing activity when combined with CD3-engaging tumor-targeting bispecific DART molecules. Methods: TRIDENT molecules were constructed comprising bivalent CD137 binding and monovalent 5T4 binding. Binding properties were evaluated by surface plasmon resonance (SPR) and flow cytometry. Signaling was assessed using a NF-κB luciferase reporter cell line expressing CD137. Co-stimulatory activity was characterized with primary human or cynomolgus monkey T cells. T cells were incubated with or without antigen-expressing cells and submaximal concentrations of either anti-CD3 bead or CD3-engaging tumor-targeting bispecific DART molecules. Results: SPR and flow cytometry analyses demonstrate that 5T4 x CD137 x CD137 TRIDENT molecule binds human and monkey target antigens. The 5T4 x CD137 x CD137 TRIDENT molecule induces CD137 signaling in a reporter cell line and promotes cytokine release in primary human & cynomolgus monkey T-cell assays in the presence of 5T4+ tumor cells. In the absence of 5T4+ tumor cells, the TRIDENT molecule lacks agonistic activity. Furthermore, 5T4 x CD137 x CD137 TRIDENT molecule enhances T-cell proliferation and tumor cell cytolysis induced by CD3-targeted DART molecules. Consistent with preferential induction of CD137 by CD8 T-cells, 5T4 x CD137 x CD137 TRIDENT increases the fraction of CD8+ central memory and effector memory T cells in the presence 5T4+ tumor cells. Conclusions: 5T4 x CD137 x CD137 TRIDENT molecule promotes T-cell co-stimulation in a tumor antigen-dependent manner offering an opportunity to target CD137 immunostimulation, while potentially limiting non-specific systemic T-cell activation and related side effects. Citation Format: Liqin Liu, Ling Huang, Vatana Long, Yinhua Yang, Robert Burns, Jonathan Li, Jennifer DiChiara, Qihong Xu, Arin Whiddon, Chia-Ying K Lam, Jim Tamura, Valentina Ciccarone, Syd Johnson, Ezio Bonvini, Paul Moore. Tumor-antigen 5T4-dependent activation of the CD137 costimulatory pathway by bispecific 5T4 x CD137 x CD137 TRIDENT™ molecules [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 554.

Strange Bird: The Albatross Press and the Third Reich by Michele K. Troy

Reviewed by: Strange Bird: The Albatross Press and the Third Reich by Michele K. Troy Paul Moore Strange Bird: The Albatross Press and the Third Reich. By Michele K. Troy. New Haven, CT: Yale University Press, 2017. Pp. 440. Cloth $40.00. ISBN 978-0300215687. Recalling his trip to Berlin in 1934, British author, artist, and sometime Hitler admirer Percy Wyndham Lewis noted "the Albatross editions I saw everywhere" (5). The ubiquity noted by Lewis seems surprising at first glance—the Albatross Press had specialized in publishing works of Anglo-American literary modernism for the continental market, in English, since 1932. Later a model for Penguin Books, the firm built a reputation for publishing cutting-edge literature at affordable prices, its offerings including works banned in the English-speaking world, such as James Joyce's Ulysses and D.H. Lawrence's Lady Chatterley's Lover. The house won the contract to publish "Lady C" four days before Hitler became Chancellor (62). This now-forgotten publishing house was able to survive and thrive under a regime that railed publicly against "un-German" culture and held books in translation to be "an insidious channel of dangerous ideas [and] a failure of patriotism on the part [End Page 168] of German readers," as one official fulminated in 1938 (157). Yet sales in Germany represented a third of the Albatross Press's total market by the late 1930s. How this situation could be, and the negotiations and compromises required to bring it about, is the subject of Michele Troy's richly detailed volume on the Albatross Press. Troy's avowedly transnational history of the business and its personalities is written with flair, and very well researched—her bibliography lists twenty-eight archives in seven countries, as well as seven similarly dispersed private collections. Among the wealth of information on the key personalities of Albatross Press and their relationships with each other, the somewhat slippery figure of John Holroyd-Reece stands out. Symptomatic of the times is the fact that his international dealings called him to the attention of the French Secret Service, which opened a file on him as a suspected German agent in 1937. Troy's sympathetic portrayal makes clear that his personal charm, ambition, and skill, as well as his "well-honed amorality" (324), were necessary to exploit the regime's economic and ideological priorities for the survival of the business. The reader is tempted to judge Holroyd-Reece more harshly than Troy herself does, given her account of him browbeating an associate-turned-rival while the latter was in a hospital bed after being hit by car, and indeed her admission, at the book's end, that it remains unclear whether Albatross ever "turned a profit on his watch" (325). Indeed, little in this book will disabuse readers inclined to see the 1930s, with W.H. Auden, as a "low, dishonest decade." Even prior to Hitler's chancellorship, a German competitor used xenophobic and antisemitic innuendo in an unedifying attempt to snuff out their nascent rivals. For the Nazi regime, it was useful to cultivate the market for English-language books as a much-needed source of foreign currency; in this way, Troy argues, "Nazi censorship [was] as much economic as moral" (101). Yet such tolerance extended only so far, with the vigilance of Nazi newspapers such as Der Stürmer leading to Albatross offerings by Jewish authors being banned and the regime blocking the firm's takeover of its German competitor due to the former's "foreign owners" (78). Troy also reveals a degree of self-censorship on the part of the publishers, making substantial cuts to Aldous Huxley's Beyond the Mexique Bay (1934) and removing its more explicit criticisms of Hitler's regime to ensure that at least an abridged version of the book could enter the German market. Its initial run of 12,000 copies sold out. Just as important as the export trade and accommodations with the government to the survival of the Albatross Press was the well-known factionalism of the Nazi hierarchy and "fragmentation" of its bureaucracy. Troy emphasizes, as have historians such as Erhard Bahr and Guenter Lewy, that "multiple government factions struggled...

The 2016 G. Paul Moore Lecture: Lessons in Voice Rehabilitation: Journal of Voice and Clinical Practice

This Paul Moore Lecture honors the contributions made by authors to the Journal of Voice during a period of 30 years, from 1987. Fifty articles were selected and included under the following five topics: (1) normalcy of the larynx and voice; (2) the clinical speech-language pathologist's evaluation; (3) the patient's perspective; (4) the core of vocal rehabilitation; and (5) behavioral versus organic dysphonias. The analysis reflects a vivid landscape of the specific area and significant advances in knowledge. It also shows the valuable interdependence between science and clinical practice. The topics highlight the following information: (1) The physical appearance of a healthy larynx varies across individuals with normal voices. (2) The voice is not a binary descriptor (normal versus abnormal) but a variable measure, with many cultural influences on the perceptual auditory analysis of a voice. (3) The clinical speech-language pathologist assessment is multidimensional and multiparametric, with both subjective and objective analyses. The patients' opinion about the impact of a voice problem on his or her quality of life is significant when proposing a treatment. Therefore, it is also included in the initial assessment. (4) Vocal rehabilitation is a nonlinear process that combines direct and indirect approaches. Evidence of the positive effect of voice therapy is now well established. (5) Behavioral dysphonias may be linked to self-regulation of the use of voice and this needs to be taken into consideration. Although organic dysphonias are not necessarily the result of harmful vocal behaviors, they too can benefit from vocal rehabilitation.

Abstract 4608: A 5T4 x CD3 bispecific DART® molecule with extended half-life for T-cell immunotherapy of cancers

Abstract Introduction: 5T4 (trophoblast glycoprotein), an oncofetal antigen involved in embryo development, is expressed on the cell surface of multiple cancers. Several 5T4-directed interventions have been reported, including a cancer vaccine and an antibody-drug conjugate. A superantigen-driven redirected cell killing modality was also developed, but obstacles, such as immunogenicity, remain to a successful 5T4 therapeutic molecule. We have developed an Fc-bearing 5T4 x CD3 DART® bispecific protein designed to redirect T cells to target 5T4-expressing tumors. Methods: 5T4 x CD3, a humanized Fc-bearing DART molecule, was stably expressed in CHO cells and purified to homogeneity via a standard antibody-purification platform. In vitro characterization and functional studies were performed with 5T4-positive tumor cell lines and human T cells. In vivo studies were performed in immune-deficient tumor-bearing mice co-implanted with activated human T cells or reconstituted with human peripheral blood mononuclear cells (PBMCs). Pharmacokinetic studies were performed in both human FcRn transgenic mice and cynomolgus monkeys. Results: 5T4 x CD3 demonstrated bispecific binding properties to both human and cynomolgus monkey antigens. In redirected cytolysis studies, 5T4 x CD3 mediated lysis of 5T4-positive pancreatic, lung, renal, triple-negative breast, and ovarian cancer cell lines with EC50 values ranging between 0.03 and 0.08 ng/mL. 5T4 x CD3 displayed favorable pharmacokinetics with a prolonged circulating half-life in human FcRn transgenic mice and cynomolgus monkeys. Tumor clearance studies in NOD/SCID mice implanted subcutaneously with activated human T cells and tumor cells demonstrated robust inhibition of tumor growth upon intravenous administration of 5T4 x CD3 at doses as low as 0.8 μg/kg, but not with a CD3-binding control DART protein. In addition, human PBMC-reconstituted NOD/SCID/IL2 gamma-chain null mice were implanted intradermally with renal and pancreatic tumor cell lines or orthotopically with a triple-negative breast cancer line and, after tumor establishment, were treated with 5T4 x CD3. Anti-tumor activity was observed at doses as low as 4 μg/kg. Immunohistochemical analysis of tumor xenografts confirmed tumor clearance was associated with T-cell recruitment into the tumor mass. Conclusions: In summary, 5T4 x CD3 displays robust antitumor activity against several cancer cell lines in vitro and in vivo together with a favorable pharmacokinetic profile and merits further consideration as a potential treatment for 5T4-positive cancers. Citation Format: Ling Huang, Gurunadh Chichili, Ralph Alderson, Francine Chen, Jennifer Brown, Hua Li, Valentina Ciccarone, Jim Tamura, Daorong Liu, Liqin Liu, Syd Johnson, Ezio Bonvini, Paul Moore. A 5T4 x CD3 bispecific DART® molecule with extended half-life for T-cell immunotherapy of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4608. doi:10.1158/1538-7445.AM2017-4608

Abstract 3642: Tumor-antigen expression-dependent activation of the CD137 costimulatory pathway by bispecific DART® proteins

Abstract Introduction: CD137 (4-1BB) is a co-stimulatory molecule expressed by activated T and NK cells that, upon interaction with its CD137 ligand, further supports cell activation, proliferation and survival. Activation via CD137 holds great promise for cancer immunotherapy; however, current CD137 agonistic interventions are associated with systemic safety concerns. To develop a therapeutic modality that reduces the potential for systemic CD137 effects, we applied the DART® bispecific platform to generate proteins that can induce tumor-antigen dependent T-cell activation. Methods: DART molecules were constructed containing anti-CD137 variable regions together with either anti-HER2 or anti-EphA2 variable regions. DART binding properties were evaluated by ELISA or flow cytometry; signaling responses assessed using a NF-κB luciferase reporter cell line expressing CD137. Co-stimulatory activity was characterized with primary human T cells in the presence or absence of tumor target antigen-expressing cells. Results: ELISA and flow cytometry analysis demonstrated that both HER2 x CD137 and EphA2 x CD137 DART molecules bind their respective target antigens. Co-culturing of a CD137/NF-κB reporter cell line with tumor lines expressing HER2 or EphA2 revealed tumor antigen-dependent CD137 pathway activation by HER2 x CD137 and EphA2 x CD137 DART molecules, respectively. To evaluate the effects of HER2 x CD137 and EphA2 x CD137 DART molecules on T-cell responses, co-stimulation T-cell assays were performed. In the presence of the relevant antigen-positive cell line, each respective DART molecule was able to promote T-cell proliferation and cytokine release in a HER2 or EphA2-dependent manner. No T-cell co-stimulation was observed by either DART molecule in the absence of antigen-expressing tumor cells. Furthermore, the level of tumor antigen-dependent co-stimulation supported by the DART molecules correlated with the level of tumor target expression. Consistent with the preferential induction of CD137 by the CD8 T cell subset, CD137-based DART proteins induced a substantial increase in the fraction of CD8+ central memory and effector memory T cells in the presence of the proper tumor antigen expressing cells. Conclusions: HER2 x CD137 and EphA2 x CD137 DART proteins promote T-cell co-stimulation in a tumor antigen-dependent manner and may provide an opportunity to target the CD137 co-stimulatory pathway for cancer immunotherapy, while limiting systemic T-cell activation and related side effects. Citation Format: Liqin Liu, Chia-Ying K. Lam, Vatana Long, Lusiana Widjaja, Yinhua Yang, Kalpana Shah, Doug Smith, Joanna Pan, Syd Johnson, Ezio Bonvini, Paul Moore. Tumor-antigen expression-dependent activation of the CD137 costimulatory pathway by bispecific DART® proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3642. doi:10.1158/1538-7445.AM2017-3642

Abstract 1489: Development of a humanized ROR1 x CD3 bispecific DART® molecule for the treatment of solid and liquid tumors

Abstract Introduction: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in chronic lymphocytic leukemia and a subset of solid tumors, including lung, breast, ovarian, colon, and pancreatic cancers, as well as sarcoma. Limited adult tissue expression and its absence in normal leukocytes makes ROR1 a promising cancer therapeutic target. We have developed a Dual-Affinity Re-Targeting (DART®) protein for redirecting T lymphocytes to lyse tumor cells via monovalent recognition of ROR1 on tumors and CD3 on T cells. ROR1 x CD3 DART protein was engineered for improved half-life with the incorporation of a modified Fc domain, lacking effector function. Methods: The ROR1 x CD3 DART protein was stably expressed in CHO cells and purified to homogeneity by a standard antibody platform. Bispecific binding was evaluated by ELISA and SPR analysis. In vitro functional studies were performed with lymphoma and solid tumor cell lines in the presence of primary human T cells. Tumor growth inhibition was evaluated in NOD/SCID/IL-2 gamma chain KO (NOG) mice coimplanted with human T cells and either mantle cell lymphoma (MCL) or lung cancer cell lines (5:1 effector : target cell ratio) followed by treatment with ROR1 x CD3 DART protein by intravenous (IV) administration. In vivo activity was also evaluated in human PBMC-reconstituted NOG/B2m deficient mice bearing established intradermal tumor xenografts following IV treatment with ROR1 x CD3 DART molecule. Pharmacokinetic analysis of the DART molecule was performed in human neonatal Fc receptor (hFcRn) transgenic mice. Results: The ROR1 x CD3 DART protein displayed the expected bispecific binding for ROR1 and CD3 antigens and retained the affinity and specificity of the parent mAbs. The DART molecule mediated dose-dependent lysis of ROR1-positive MCL and solid tumor (breast, lung, and osteosarcoma) cell lines through recruitment of human T cells. DART molecule-mediated killing of ROR1-expressing target cells was accompanied by target-dependent T-cell activation and cytokine release; however, no activity was observed in the absence of target cells and no cytokine release was observed with human PBMCs alone. The ROR1 x CD3 DART protein displayed extended circulating half-life after administration to hFcRn-transgenic mice. In mouse efficacy studies, the growth of HBL-2 (MCL), HOP-92 (lung cancer), or NIH-1975 (a lung cancer line resistant to erlotinib) cells co-implanted with human T cells in NOG mice was inhibited by treatment with the ROR1 x CD3 DART protein at doses in the mcg/kg range. The ROR1 x CD3 DART molecule also demonstrated antitumor activity with high complete response rates in human PBMC-reconstituted mice bearing established HBL-2 cell xenografts. Conclusion: The promising in vitro and in vivo activity of the Fc-bearing ROR1 x CD3 DART molecule supports further investigation as a potential candidate for the cancer treatment. Citation Format: Bhaswati Barat, Gurunadh Chichili, Valentina Ciccarone, James Tamura, Sergey Gorlatov, Michael Spliedt, Francine Chen, Scott Koenig, Paul Moore, Ezio Bonvini, Ralph Alderson, Syd Johnson. Development of a humanized ROR1 x CD3 bispecific DART® molecule for the treatment of solid and liquid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1489.

Abstract 1498: Development of an IL13Ralpha2 x CD3 bispecific DART® protein for redirected T-cell killing of solid tumors

Abstract Introduction. IL13Rα2 is a membrane-bound protein expressed on a number of malignant tumors, but not at significant levels in most normal tissues. Clinically tested therapies to treat cancer by targeting IL13Rα2 to date have included a ligand toxin conjugate (IL13-PE) and IL13Rα2 directed CAR-T cells. Both strategies appear to be well tolerated, although with mixed results in tumor eradication. An alternative strategy for targeting IL13Rα2 is an IL13Rα2 x CD3 Dual-Affinity Re-Targeting (DART®) bispecific molecule designed to co-engage IL13Rα2 on tumor cells and cytotoxic T cells through CD3, resulting in killing of tumor cells. Methods. Mouse monoclonal antibodies (mAbs) were generated using standard immunization protocols followed by binding and epitope binning analyses. Cell binding was performed by flow cytometry and frozen normal and tumor tissues analyses by immunohistochemistry (IHC). In vitro studies were performed with cancer cell lines and primary human T cells or peripheral blood mononuclear cells (PBMCs). In vivo studies were performed in immune-deficient tumor-bearing mice co-implanted with activated human T cells or reconstituted with human PBMCs. Results. A panel of mAbs that bind human and cynomolgus monkey IL13Rα2 proteins were selected, representing a range of binding characteristics and epitope diversity. IHC showed favorable normal vs tumor tissue reactivity, with high levels of IL13Rα2 expression in glioblastoma and melanoma. The mAb panel was converted to DART molecules with an anti-CD3 arm, assessed for the ability to mediate cytotoxic T lymphocyte (CTL) activity and cytokine release and a lead selected for humanization and engineering into an IL13Rα2 x CD3 DART molecule incorporating an Fc domain to prolong circulating half-life. The IL13Rα2 x CD3 DART protein bound human and cynomolgus IL13Rα2 (KD = 0.64 nM and 0.5 nM, respectively) and mediated CTL activity against LOX-IMVI (melanoma) and SK-MES-1 (lung adenocarcinoma) target cells. Cytokines (IFN-γ, IL-10, and TNF-α) were released in the presence of IL13Rα2-expressing target cells and human PBMC, but not with PBMCs alone. Administration of the IL13Rα2 x CD3 DART molecule (≤50 μg/kg IV for 4 consecutive days) prevented tumor growth when tumor cells (A375 and LOX-IMVI melanoma, U87 glioblastoma, or DAOY medulloblastoma cell lines) were co-mixed with activated human T cells and implanted subcutaneously in NOD/SCID/IL2gamma-chain null mice. Tumor eradication was also observed in NOD/SCID/IL2gamma-chain/MHCI KO mice reconstituted with human PBMCs and bearing established LOX-IMVI melanoma tumors following 2 weekly IV doses of 50 μg/kg IL13Rα2 x CD3 DART molecule. Conclusions: Robust in vitro and in vivo antitumor activity for an IL13Rα2 x CD3 DART protein was demonstrated. Additional studies are underway to further characterize the molecule as a development candidate for treatment of IL13Rα2-positive cancers. Citation Format: Jill Rillema, Monica Licea, Shereen Saini-Lal, Doug Smith, Francine Chen, Annie Lam, Yinhua Yang, Liqin Liu, James Tamura, Ralph Alderson, Ezio Bonvini, Syd Johnson, Paul Moore. Development of an IL13Ralpha2 x CD3 bispecific DART® protein for redirected T-cell killing of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1498.

Abstract 583: Evaluation of EphA2 as a therapeutic target for redirected T-cell killing by DART® bispecific molecules

Abstract Introduction: EphA2 is a receptor tyrosine kinase that plays a critical role in cancer progression through both ligand-dependent and independent mechanisms. The broad overexpression in tumors but limited normal tissue expression of EphA2 makes it an attractive therapeutic target amenable for redirected T-cell killing via an EphA2 x CD3 Dual-Affinity Re-Targeting (DART®) molecules designed to co-engage cytotoxic T cells with EphA2 expressing tumor cells. Methods: Anti-EphA2 monoclonal antibodies (mAbs) were identified by target-specific screening of a library generated by whole-cell immunization with proprietary cancer cell lines, including models of cancer stem cells. The binding and signaling properties of the antibodies were characterized by ELISA, SPR, flow cytometry and phosphorylation assays. Receptor binding regions were determined by ELISA based competition assays and by utilizing human-mouse chimeric EphA2 molecules. Immunohistochemistry (IHC) was performed on frozen normal and tumor tissues. In vitro functional studies were performed with various cancer as well as transfected cell lines, and primary human T cells or PBMCs. In vivo activity was evaluated in xenograft models in immune deficient mice. Results: EphA2 mAbs encompassing diversity in binding kinetics and effects on receptor phosphorylation were classified in 5 discrete binding groups. The majority interacted with the N-terminal ligand-binding domain of EphA2 and most mAbs within that group interfered with ligand binding. The majority of mAbs displayed little IHC reactivity with normal tissue, while strong staining of cancer tissues was observed, including colon, lung, pancreas, ovary, bladder and breast cancers. Seven mAbs recognizing independent epitopes were selected for conversion into EphA2 x CD3 DART molecules that showed a range of potency in redirecting T cells to kill EphA2-expressing target cells. A lead EphA2 x CD3 DART molecule was selected based on potency and cross-reactivity with the cynomolgus monkey ortholog; this lead was engineered with a human Fc domain to confer an extended circulating half-life. The resulting Fc-bearing EphA2 x CD3 DART molecule demonstrated in vivo anti-tumor activity at doses as low as 20 mcg/kg in NOD/SCID/IL-2 gamma chain null mice co-implanted with activated human T cells and MDA-MB231 breast cancer cells. Conclusion: EphA2 is a potential cancer target for redirected T-cell killing applications independent of ligand mediated mechanisms. Further preclinical assessment of EphA2 x CD3 DART molecules as a strategy for targeting EphA2-expressing malignancies is warranted. Citation Format: Claudia B. Fieger, Kalpana Shah, Gurunadh Chichili, Jonathan Li, Thomas Son, Jeffrey Hooley, Francine Chen, Sergey Gorlatov, Steve Burke, Valentina Ciccarone, Ralph Alderson, Deryk Loo, Syd Johnson, Ezio Bonvini, Paul Moore. Evaluation of EphA2 as a therapeutic target for redirected T-cell killing by DART® bispecific molecules. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 583.

Abstract 3217: MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment

Abstract Introduction: The combination of monoclonal antibodies (mAbs) that targets the immune checkpoint molecules CTLA-4 and PD-1 has shown clinical benefit beyond that observed with either mAb alone. This finding has prompted exploring whether such an approach could be applied within the context of additional combinations of checkpoint molecules, such as PD-1 and lymphocyte activation gene-3 (LAG-3). Animal tumor models have validated combining anti-PD-1 with anti-LAG-3 mAbs in eliciting synergistic tumor-eradicating immunity; expression of PD-1 and LAG-3 on exhausted T cells and tumor infiltrating lymphocytes (TILs) further supports their dual-targeting. We have developed a bispecific DART® protein that targets PD-1 and LAG-3, aimed at inducing potent antitumor immunity through simultaneous blockade of non-redundant checkpoint pathways intrinsic to exhausted T cells. Methods: mAbs against PD-1 and LAG-3 were generated and selected for DART conversion based on binding, biophysical and functional blocking against their respective receptor/ligand axes and functional activity in re-activation of prior superantigen-stimulated T cells or in antigen-specific recall assays. Results: Lead PD-1 and LAG-3 mAbs demonstrating favorable functional properties were selected for humanization. Immunohistochemistry confirmed that the lead LAG-3 and PD-1 mAbs display restricted lymphocyte expression in human tissues and overlapping expression in TILs. The humanized mAbs were assembled into MGD013, an Fc-bearing PD-1 x LAG-3 DART protein that demonstrated favorable biophysical and manufacturability properties. MGD013 bound specifically with high affinity to PD-1 and LAG-3 as well as to target-expressing cell lines and chronically-activated T cells. MGD013 blocked PD-1/PD-L1, PD-1/PD-L2 and LAG-3/HLA (MHC-II) interactions and PD-1 signaling. Further functional characterization of MGD013 revealed enhanced cytokine secretion in response to antigenic re-challenge of previously stimulated T cells compared to that observed upon independent blockade of either the PD-1 or LAG-3 pathways alone. Furthermore, under the above experimental conditions, MGD013 mediated greater cytokine secretion than that observed with the combination of equivalent (equimolar) levels of replicas of the approved PD-1 mAb, nivolumab, and the LAG-3 mAb, 25F7, which is currently undergoing clinical testing. Finally, cynomolgus monkey pharmacokinetic studies demonstrated a prolonged circulating half-life consistent with that of an Fc-bearing molecule. Conclusions: MGD013 blocks both PD-1 and LAG-3 pathways, resulting in enhanced T-cell responses compared to single or combination mAb blockade. Together with favorable cynomolgus monkey PK, these studies support further clinical development of MGD013. Citation Format: Ross LaMotte-Mohs, Kalpana Shah, Doug Smith, Sergey Gorlatov, Valentina Ciccarone, James Tamura, Hua Li, Jill Rillema, Monica Licea, Leilei He, Farha Vasanwala, Wei Chen, Xiao-Tao Yao, Francine Chen, Jennifer Brown, Jeffrey Nordstrom, Scott Koenig, Ezio Bonvini, Syd Johnson, Paul Moore. MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3217.

Researchers set out to counter behavioural biometrics

Researchers Per Thorsheim and Paul Moore have been working on a Chrome browser plug-in, designed to counter behavioural biometrics by obscuring the digital trail left by behavioural biometrics.

Abstract 2476: Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors

Abstract Introduction: Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a Dual-Affinity Re-Targeting (DART®) protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of P-cadherin expressing tumors. We designate this bispecific redirecting T-cell molecule as P-cadherin LP-DART. P-cadherin up-regulation has been reported in various tumors, including breast, gastric, endometrial, colorectal and pancreatic cancers, and is correlated with poor survival of patients. Methods: The P-cadherin LP-DART was stably expressed by CHO cells and purified to homogeneity via standard antibody-purification methods. Functional in vitro studies were performed with a panel of human cancer cell lines and human T cells isolated from healthy donors. In vivo tumor growth inhibition studies were performed in immunodeficient athymic nude or NOD-scid IL2Rgammanull (NSG) mice bearing human tumor cell line- or patient derived-xenografts and human T-cells, and treated with P-cadherin LP-DART. Results: P-cadherin LP-DART exhibited binding to a broad panel of cancer cell lines expressing various levels of endogenous cell surface P-cadherin, and comparable binding to a number of human donor derived T-cells expressing CD3. In the presence of T-cells, this bispecific molecule elicited P-cadherin expression level dependent cytotoxic T-lymphocyte (CTL) responses against the different tumor cell lines, and induced antigen dependent T-cell activation and cytokine release. P-cadherin LP-DART also demonstrated potent in vivo anti-tumor activity against implanted tumor xenografts. Significant tumor growth inhibition was observed across a range of potential indications that express P-cadherin. Measurement of in vivo pharmacodynamic markers support P-cadherin LP-DART mediated CTL infiltration and killing as the mechanism of tumor inhibition. Conclusions: P-cadherin LP-DART displays potent in vitro and in vivo redirected T-cell activity against a broad panel of cancer cell lines expressing a range of cell surface P-cadherin levels. These data support further investigation of P-cadherin LP-DART as a potential novel therapeutic treatment for cancers expressing P-cadherin. Citation Format: Timothy S. Fisher, Adam Root, Bryan Peano, Allison Rohner, Justin Lucas, Mark Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Susan Benard, Tao He, Tracey Clark, Nahor Haddish-Berhane, Ralph Alderson, Yinhua Yang, Syd Johnson, Paul Moore, Lioudmila Tchistiakova, Hans-Peter Gerber, Chad May. Bispecific redirected T-cell immunotherapy targeting P-cadherin expressing tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2015-2476

Verschleppt und Entwurzelt. Zwangsarbeit zwischen Soest, Werl, Wickede und Möhnetal by Mechtild Brand (review)

Reviewed by: Verschleppt und Entwurzelt. Zwangsarbeit zwischen Soest, Werl, Wickede und Möhnetal by Mechtild Brand Paul Moore Verschleppt und Entwurzelt. Zwangsarbeit zwischen Soest, Werl, Wickede und Möhnetal. By Mechtild Brand. Essen: Klartext, 2010. Pp. 330. Paper €19.95. ISBN 978-3837503777. In recent years, local historians have greatly expanded what we know of the social history of European dictatorships, notably Franco’s Spain and Mussolini’s Italy. This development is true of Germany as well, where, for the past thirty years, scholars have produced ground-breaking studies of the impact of Nazi rule on particular regions. Following from her previous work on the persecution of Roma and Sinti in her hometown of Hamm, Mechtild Brand examines Polish and Ukrainian forced laborers during the Second World War who were sent to work in the nearby Kreis (county) of Soest, a rural area in what is now North Rhine-Westphalia. Since Ulrich Herbert’s landmark study of 1985, civilian forced laborers have become the object of sustained historical research as well. Still it is not surprising that some of Brand’s sources confessed, “that they could not imagine that a book of their stories could exist” (7). One also encounters this poignant, yet common, assertion from former forced laborers in other recent books on the subject, notably Alexander von Plato’s volume Hitler’s Slaves (2010). Like that book, Brand’s study was made possible through the cooperation of national organizations dedicated to reconciliation and restitution in Poland and Ukraine who put her into contact with former forced laborers; their autobiographical reports represent Brand’s main source base. Placing the moral aspect at the heart of her study, Brand concludes that the diversity of experience encountered by the Poles and Ukrainians was attributable above all to the similarly varied “decisions [made by] every individual” German—the “personal responsibility” of ordinary civilians (309). In the Third Reich and the occupied territories combined, about 13.5 million people—camp inmates and POWs as well as the civilians Brand analyses—were exploited during the war by the Nazi regime as forced laborers. By mid-1944, foreign workers represented well over ten percent of the total population nationally. While conceding the difficulty of establishing precise numbers, Brand concludes that Kreis Soest was no different, with around 8,000 forced laborers among a regional population of about 73,000. Potential employers inspected the new arrivals at the local employment [End Page 208] office before choosing “their” Eastern Europeans in a process remembered decades later as a “cattle [or] slave market” (32). The majority of Brand’s subjects worked in agriculture, on farms or in workshops. They typically came into contact with locals and employers as a result and were often treated relatively well. In the towns of Soest and Werl, however, as well as the industrial area of Wickede, the work was provided by factories and firms. These forced laborers were separated from the German population to a much greater extent, and their accommodation in barracks in itself resulted in more desperate living conditions. Brand is careful not to neglect the violent aspects of her story. In a new discovery, for example, the book recounts the execution of eighteen Russian laborers in the last days of the war. Yet the full diversity of experience is also conveyed. Brand’s subjects took care to discriminate when it came time for vengeance with the war’s end: they protected homesteads, businesses, and individuals from attack in numerous cases just as often as they identified suitable targets for retribution. Some locals kept in touch with “their” Eastern Europeans for years after the war, with contact extending in some cases to the time of Brand’s writing; others kept photographs of them in the family album. These practices coexisted with a highly selective collective memory. “Over a long period,” Brand writes, “hundreds of abductees were driven through [Soest] on a regular basis, and could not be overlooked by the population.” Yet few anecdotes from the locality itself attest to this fact (31). At the outset Brand admits to a certain commemorative impulse. The inside jacket shows the former forced laborers in the present, and the text nods to giving...

Whistleblowing, Governance and Regulation Before the Financial Crisis: The Case of HBOS

Following the financial crisis of 2008, the Treasury Committee of the UK House of Commons undertook an inquiry into the lessons that might be learned from the banking crisis. Paul Moore, head of group regulatory risk at Halifax Bank of Scotland (HBOS) during 2002–2005, provided evidence of his experience of questioning HBOS policies which resulted in his dismissal from HBOS. The problems that surfaced at HBOS during the financial crisis were so serious that it was forced to merge with Lloyds TSB, another UK bank, to form the Lloyds Banking Group in which the government took a significant stake. Moore’s evidence to the Treasury Committee revealed that long before the financial crisis, he had raised major concerns with the management of HBOS and with the Financial Services Authority (FSA), the UK financial services regulator. Moore’s evidence led to the submission of further disclosures, replies and rejoinders as evidence to the Treasury Committee. Moore’s case is therefore of considerable interest to researchers of whistleblowing because it is a rare instance of high-level whistleblowing, the details of which subsequently entered the public domain. The information revealed in evidence to the Treasury Committee sheds light on the process of whistleblowing in the context of the governance and regulation of a major UK bank that subsequently had to be rescued by government intervention during the financial crisis. The paper makes a contribution to the wider literature on whistleblowing, and to a greater understanding of aspects of the financial crisis.