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"Martin, Stephen L"
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Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations
BackgroundOX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.MethodsAnti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.ResultsIsotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.ConclusionsThese findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.
Journal Article
“Healing and creating” in economic ethics: Christian ethics, social economics, and Bernard Lonergan, in conversation
This dissertation examines the use of economic theory in contemporary Christian social and economic ethics, arguing that the dominant stress on either neoclassical or Marxian economic theory within economic ethics is problematic due to inherent difficulties with religious ethics with each paradigm. I propose two alternative sources of dialogue. The first is social (or humanitarian) economics, a tradition within economics opposed to the religiously suspicious anthropologies of “economic man” in neoclassical economic, yet not tied the Marxian reliance on dialectical materialism or class conflict. The second is the thought of Bernard Lonergan, whose recently published Macroeconomic Dynamics: An Essay in Circulation Analysis, written originally from 1930–1944, offers an alternative paradigm to neo-classical and Marxian paradigms, and one more in keeping with Christian anthropology. In Part One I critically analyze important selected uses of economic theory in contemporary religious ethics, especially in modern Catholic social thought, examining how incoherencies and conflicts between economic and religious ethical descriptions and evaluations of human behavior and social processes mar the effectiveness of Christian moral argumentation concerning economic matters. Part Two examines the normative or ethical dimensions and commitments of current economic approaches (neo-classical, liberal and Marxian). I also investigate how social economics seeks to integrate views of the human person alternative to economic man and social economics' openness to explicit normative dimensions. However, social economics has not yet provided a powerful enough macroeconomic explanatory paradigm to replace the dominant approaches. In Part Three, I also examine Lonergan's view of the human person and economic agent as an alternative to the economic anthropology in existing economic theory. Furthermore, I propose his critical science of economics as found in Essay in Circulation Analysis as an alternative and more scientifically explanatory macroeconomic paradigm than currently found in any type of economics. In conclusion, in conversation with Catholic social thought, social economics and Lonergan's economic thought, I begin to describe the lineaments of a Christian economic ethics that overcomes these incoherencies and reflects an effective and mutual partnership between economics and religious ethics.
Dissertation
International Olympic Committee consensus statement: methods for recording and reporting of epidemiological data on injury and illness in sport 2020 (including STROBE Extension for Sport Injury and Illness Surveillance (STROBE-SIIS))
Injury and illness surveillance, and epidemiological studies, are fundamental elements of concerted efforts to protect the health of the athlete. To encourage consistency in the definitions and methodology used, and to enable data across studies to be compared, research groups have published 11 sport-specific or setting-specific consensus statements on sports injury (and, eventually, illness) epidemiology to date. Our objective was to further strengthen consistency in data collection, injury definitions and research reporting through an updated set of recommendations for sports injury and illness studies, including a new Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist extension. The IOC invited a working group of international experts to review relevant literature and provide recommendations. The procedure included an open online survey, several stages of text drafting and consultation by working groups and a 3-day consensus meeting in October 2019. This statement includes recommendations for data collection and research reporting covering key components: defining and classifying health problems; severity of health problems; capturing and reporting athlete exposure; expressing risk; burden of health problems; study population characteristics and data collection methods. Based on these, we also developed a new reporting guideline as a STROBE Extension—the STROBE Sports Injury and Illness Surveillance (STROBE-SIIS). The IOC encourages ongoing in- and out-of-competition surveillance programmes and studies to describe injury and illness trends and patterns, understand their causes and develop measures to protect the health of the athlete. Implementation of the methods outlined in this statement will advance consistency in data collection and research reporting.
Journal Article