Metabolic modulation of tumours with engineered bacteria for immunotherapy.

The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response1-4. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.

Striatal Dopamine Contributions to Skilled Motor Learning.

Coordinated multijoint limb and digit movements-"manual dexterity"-underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that corticostriatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release in both male and female mice as they learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In the dorsolateral striatum, dopamine dynamics are faster than in the dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of the striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage.

The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3(+) regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3(+) Treg cells in Aire(+/+) mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells.

Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells.

Although antigen recognition mediated by the T cell receptor (TCR) influences many facets of Foxp3(+) regulatory T (Treg) cell biology, including development and function, the cell types that present antigen to Treg cells in vivo remain largely undefined. By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we demonstrated an essential role for dendritic cells (DCs) in regulating organ-specific Treg cell biology. We have shown that the thymic development of prostate-specific Treg cells required antigen presentation by DCs. Moreover, Batf3-dependent CD8α(+) DCs were dispensable for the development of this clonotype and had negligible impact on the polyclonal Treg cell repertoire. In the periphery, CCR7-dependent migratory DCs coordinated the activation of organ-specific Treg cells in the prostate-draining lymph nodes. Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy.

OBJECTIVES: DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions. METHODS: Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice. RESULTS: Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic-clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. INTERPRETATION: Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023;94:812-824.

Risk factors for intensive care unit admission and death from COVID-19 in fully vaccinated patients hospitalized for severe COVID-19, Brazil, 2021-2022.

Objectives: To assess factors associated with admission to an intensive care unit (ICU) and death from coronavirus disease 2019 (COVID-19) in fully vaccinated patients with severe COVID-19 in Brazil and the association between ICU admission and death from COVID-19. Methods: This was retrospective study of patients hospitalized for COVID-19 from February 12, 2021 to January 10, 2022 across Brazil who were fully vaccinated against COVID-19 before hospitalization. Outcomes were admission in an ICU for COVID-19 and death from COVID-19. Variables evaluated were: sex; age; self-reported skin color; macroregion; comorbidities; time between full vaccination and onset of symptoms; and time between onset of symptoms and hospitalization. A Poisson regression model was used to estimate crude and adjusted risk ratios. Results: Of 74 991 patients hospitalized for severe COVID-19, 67.28% were ≥ 70 years and 68.32% had at least one comorbidity. Men, patients aged 60-69 years, and patients aged 18-39 years with obesity had the greatest risk of ICU admission. Patients aged 18-39 years with obesity, diabetes, or renal diseases had the highest risk of death from COVID-19. When age and time between onset of symptoms and hospitalization were considered effect modifiers, patients admitted to an ICU 9-13 days after symptom onset in each age category had the greatest risk of death from COVID-19. Conclusion: Although older patients were at greatest risk of ICU admission and death from COVID-19, the difference in the risk of dying from COVID-19 between patients admitted to an ICU and those not admitted was greatest for young adults.

Negligible Role for Deletion Mediated by cDC1 in CD8+ T Cell Tolerance.

Deletion of CD8+ T cells by dendritic cells (DCs) is recognized as a critical mechanism of immune tolerance to self-antigens. Although DC-mediated peripheral deletion of autoreactive CD8+ T cells has been demonstrated using T cells reactive to model Ags, its role in shaping the naturally occurring polyclonal CD8+ T cell repertoire has not been defined. Using Batf3-/- mice lacking cross-presenting CD8α+ and CD103+ DCs (also known as type 1 conventional [cDC1]), we demonstrate that peripheral deletion of CD8+ T cells reactive to a model tissue Ag is dependent on cDC1. However, endogenous CD8+ T cells from the periphery of Batf3-/- mice do not exhibit heightened self-reactivity, and deep TCR sequencing of CD8+ T cells from Batf3-/- and Batf3+/+ mice reveals that cDC1 have a minimal impact on shaping the peripheral CD8+ T cell repertoire. Thus, although evident in reductionist systems, deletion of polyclonal self-specific CD8+ T cells by cDC1 plays a negligible role in enforcing tolerance to natural self-ligands.

[Maternal and child health inequalities among migrants: the case of Haiti and the Dominican RepublicDesigualdades na saúde materno-infantil entre migrantes: o caso do Haiti e da República Dominicana]. / Desigualdades en la salud maternoinfantil de los migrantes: el caso de Haití y la República Dominicana.

OBJECTIVE: To assess coverage and inequalities in maternal and child health interventions among Haitians, Haitian migrants in the Dominican Republic and Dominicans. METHODS: Cross-sectional study using data from nationally representative surveys carried out in Haiti in 2012 and in the Dominican Republic in 2014. Nine indicators were compared: demand for family planning satisfied with modern methods, antenatal care, delivery care (skilled birth attendance), child vaccination (BCG, measles and DPT3), child case management (oral rehydration salts for diarrhea and careseeking for suspected pneumonia), and the composite coverage index. Wealth was measured through an asset-based index, divided into tertiles, and place of residence (urban or rural) was established according to the country definition. RESULTS: Haitians showed the lowest coverage for demand for family planning satisfied with modern methods (44.2%), antenatal care (65.3%), skilled birth attendance (39.5%) and careseeking for suspected pneumonia (37.9%), and the highest for oral rehydration salts for diarrhea (52.9%), whereas Haitian migrants had the lowest coverage in DPT3 (44.1%) and oral rehydration salts for diarrhea (38%) and the highest in careseeking for suspected pneumonia (80.7%). Dominicans presented the highest coverage for most indicators, except oral rehydration salts for diarrhea and careseeking for suspected pneumonia. The composite coverage index was 79.2% for Dominicans, 69.0% for Haitian migrants, and 52.6% for Haitians. Socioeconomic inequalities generally had pro-rich and pro-urban pattern in all analyzed groups. CONCLUSION: Haitian migrants presented higher coverage than Haitians, but lower than Dominicans. Both countries should plan actions and policies to increase coverage and address inequalities of maternal health interventions.

OBJETIVO: Avaliar cobertura e desigualdades nas intervenções em saúde materno-infantil entre os haitianos, migrantes haitianos na República Dominicana e dominicanos. MÉTODOS: Estudo transversal utilizando dados de pesquisas representativas nacionalmente realizadas no Haiti em 2012, e na República Dominicana em 2014. Nove indicadores foram comparados: demanda por planejamento familiar atendida com métodos modernos, atendimento pré-natal, atendimento ao parto (presença de profissional qualificado no parto), vacinação de crianças (BCG, sarampo e DPT3), atendimento de crianças (sais de reidratação oral para diarreia e demanda por assistência por suspeita de pneumonia) e índice composto de cobertura. A riqueza foi medida por meio de índice baseado em recursos, dividido em tercis, e o local de residência (urbano ou rural) foi estabelecido segundo a definição dos países. RESULTADOS: Os haitianos apresentaram a menor cobertura de demanda por planejamento familiar atendida com métodos modernos (44,2%), atendimento pré-natal (65,3%), presença de profissional qualificado no parto (39,5%) e de atendimento por suspeita de pneumonia (37,9%), e a mais alta para sais de reidratação oral na diarreia (52,9%), enquanto os migrantes haitianos tiveram a menor cobertura de DPT3 (44,1%) e sais de reidratação oral para diarreia (38%), e a mais alta na assistência por suspeita de pneumonia (80,7%). Os dominicanos apresentaram a cobertura mais alta para a maioria dos indicadores, exceto para sais de reidratação oral para diarreia e demanda por assistência por suspeita de pneumonia. O índice composto de cobertura foi 79,2% para dominicanos, 69,0% para migrantes haitianos e 52,6% para os haitianos. De forma geral, as desigualdades socioeconômicas apresentaram padrão pró-riqueza e pró-urbano em todos os grupos analisados. CONCLUSÕES: Os migrantes haitianos apresentaram maior cobertura que os haitianos, mas coberturas inferiores aos dominicanos. Ambos os países devem planejar ações e políticas para aumentar a cobertura e abordar as desigualdades nas intervenções em saúde materna.

Maternal and child health inequalities among migrants: the case of Haiti and the Dominican Republic.

OBJECTIVE: To assess coverage and inequalities in maternal and child health interventions among Haitians, Haitian migrants in the Dominican Republic and Dominicans. METHODS: Cross-sectional study using data from nationally representative surveys carried out in Haiti in 2012 and in the Dominican Republic in 2014. Nine indicators were compared: demand for family planning satisfied with modern methods, antenatal care, delivery care (skilled birth attendance), child vaccination (BCG, measles and DPT3), child case management (oral rehydration salts for diarrhea and careseeking for suspected pneumonia), and the composite coverage index. Wealth was measured through an asset-based index, divided into tertiles, and place of residence (urban or rural) was established according to the country definition. RESULTS: Haitians showed the lowest coverage for demand for family planning satisfied with modern methods (44.2%), antenatal care (65.3%), skilled birth attendance (39.5%) and careseeking for suspected pneumonia (37.9%), and the highest for oral rehydration salts for diarrhea (52.9%), whereas Haitian migrants had the lowest coverage in DPT3 (44.1%) and oral rehydration salts for diarrhea (38%) and the highest in careseeking for suspected pneumonia (80.7%). Dominicans presented the highest coverage for most indicators, except oral rehydration salts for diarrhea and careseeking for suspected pneumonia. The composite coverage index was 79.2% for Dominicans, 69.0% for Haitian migrants, and 52.6% for Haitians. Socioeconomic inequalities generally had pro-rich and pro-urban pattern in all analyzed groups. CONCLUSION: Haitian migrants presented higher coverage than Haitians, but lower than Dominicans. Both countries should plan actions and policies to increase coverage and address inequalities of maternal health interventions.

OBJETIVO: Evaluar la cobertura y las desigualdades en las intervenciones de salud maternoinfantil entre haitianos, migrantes haitianos en la República Dominicana y dominicanos. MÉTODOS: Estudio transversal con datos de encuestas representativas a nivel nacional realizadas en Haití en 2012 y en la República Dominicana en 2014. Se compararon nueve indicadores: demanda de planificación familiar satisfecha con métodos modernos, atención prenatal, atención del parto (por personal de salud calificado), vacunación infantil (BCG, sarampión y DPT3), gestión de casos de enfermedad en la infancia (administración de sales de rehidratación oral para la diarrea y búsqueda de atención sanitaria ante la sospecha de neumonía), e índice de cobertura compuesto. La riqueza se midió mediante un índice basado en los activos, dividido en terciles, y el lugar de residencia (urbano o rural) se determinó según la definición del país. RESULTADOS: La población haitiana mostró la menor cobertura respecto de la demanda de planificación familiar satisfecha con métodos modernos (44,2%), atención prenatal (65,3%), asistencia calificada en el parto (39,5%) y búsqueda de atención sanitaria ante la sospecha de neumonía (37,9%), y la mayor respecto de la administración de sales de rehidratación oral para la diarrea (52,9%); los migrantes haitianos presentaron la menor cobertura en DPT3 (44,1%) y la administración de sales de rehidratación oral para la diarrea (38%) y la mayor en la búsqueda de atención sanitaria ante la sospecha de neumonía (80,7%). La población dominicana presentó la cobertura más alta en la mayoría de los indicadores, excepto en la administración de sales de rehidratación oral para la diarrea y en la búsqueda de atención sanitaria ante la sospecha de neumonía. El índice de cobertura compuesto fue de 79,2% para los dominicanos, 69,0% para los migrantes haitianos y 52,6% para los haitianos. Las desigualdades socioeconómicas generalmente tenían un patrón prorrico y prourbano en todos los grupos analizados. CONCLUSIÓN: Los migrantes haitianos en la República Dominicana presentaron una mayor cobertura que la población haitiana residente en Haití, pero menor que la población dominicana. Ambos países deberían planificar acciones y políticas para aumentar la cobertura y abordar las desigualdades existentes en las intervenciones de salud materna.

Distinct Populations of Motor Thalamic Neurons Encode Action Initiation, Action Selection, and Movement Vigor.

Motor thalamus (Mthal) comprises the ventral anterior, ventral lateral, and ventral medial thalamic nuclei in rodents. This subcortical hub receives input from the basal ganglia (BG), cerebellum, and reticular thalamus in addition to connecting reciprocally with motor cortical regions. Despite the central location of Mthal, the mechanisms by which it influences movement remain unclear. To determine its role in generating ballistic, goal-directed movement, we recorded single-unit Mthal activity as male rats performed a two-alternative forced-choice task. A large population of Mthal neurons increased their firing briefly near movement initiation and could be segregated into functional groups based on their behavioral correlates. The activity of "initiation" units was more tightly locked to instructional cues than movement onset, did not predict which direction the rat would move, and was anticorrelated with reaction time (RT). Conversely, the activity of "execution" units was more tightly locked to movement onset than instructional cues, predicted which direction the rat would move, and was anticorrelated with both RT and movement time. These results suggest that Mthal influences choice RT performance in two stages: short latency, nonspecific action initiation followed by action selection/invigoration. We discuss the implications of these results for models of motor control incorporating BG and cerebellar circuits.SIGNIFICANCE STATEMENT Motor thalamus (Mthal) is a central node linking subcortical and cortical motor circuits, though its precise role in motor control is unclear. Here, we define distinct populations of Mthal neurons that either encode movement initiation, or both action selection and movement vigor. These results have important implications for understanding how basal ganglia, cerebellar, and motor cortical signals are integrated. Such an understanding is critical to defining the pathophysiology of a range of BG- and cerebellum-linked movement disorders, as well as refining pharmacologic and neuromodulatory approaches to their treatment.

Sensorimotor Processing in the Basal Ganglia Leads to Transient Beta Oscillations during Behavior.

Brief epochs of beta oscillations have been implicated in sensorimotor control in the basal ganglia of task-performing healthy animals. However, which neural processes underlie their generation and how they are affected by sensorimotor processing remains unclear. To determine the mechanisms underlying transient beta oscillations in the LFP, we combined computational modeling of the subthalamo-pallidal network for the generation of beta oscillations with realistic stimulation patterns derived from single-unit data recorded from different basal ganglia subregions in rats performing a cued choice task. In the recordings, we found distinct firing patterns in the striatum, globus pallidus, and subthalamic nucleus related to sensory and motor events during the behavioral task. Using these firing patterns to generate realistic inputs to our network model led to transient beta oscillations with the same time course as the rat LFP data. In addition, our model can account for further nonintuitive aspects of beta modulation, including beta phase resets after sensory cues and correlations with reaction time. Overall, our model can explain how the combination of temporally regulated sensory responses of the subthalamic nucleus, ramping activity of the subthalamic nucleus, and movement-related activity of the globus pallidus leads to transient beta oscillations during behavior.SIGNIFICANCE STATEMENT Transient beta oscillations emerge in the normal functioning cortico-basal ganglia loop during behavior. Here, we used a unique approach connecting a computational model closely with experimental data. In this way, we achieved a simulation environment for our model that mimics natural input patterns in awake, behaving animals. We demonstrate that a computational model for beta oscillations in Parkinson's disease (PD) can also account for complex patterns of transient beta oscillations in healthy animals. Therefore, we propose that transient beta oscillations in healthy animals share the same mechanism with pathological beta oscillations in PD. This important result connects functional and pathological roles of beta oscillations in the basal ganglia.

Shaping the repertoire of tumor-infiltrating effector and regulatory T cells.

Many tumors express antigens that can be specifically or selectively recognized by T lymphocytes, suggesting that T-cell-mediated immunity may be harnessed for the immunotherapy of cancer. However, since tumors originate from normal cells and evolve within the context of self-tissues, the immune mechanisms that prevent the autoimmune attack of normal tissues function in parallel to restrict anti-tumor immunity. In particular, the purging of autoreactive T cells and the development of immune-suppressive regulatory T cells (Tregs) are thought to be major barriers impeding anti-tumor immune responses. Here, we discuss current understanding regarding the antigens recognized by tumor-infiltrating T-cell populations, the mechanisms that shape the repertoire of these cells, and the role of the transcription factor autoimmune regulator (Aire) in these processes. Further elucidation of these principles is likely to be critical for optimizing emerging cancer immunotherapies, and for the rational design of novel therapies exhibiting robust anti-tumor activity with limited toxicity.

Basic principles of tumor-associated regulatory T cell biology.

Due to the critical role of forkhead box (Fox)p3(+) regulatory T cells (Tregs) in the regulation of immunity and the enrichment of Tregs within many human tumors, several emerging therapeutic strategies for cancer involve the depletion or modulation of Tregs, with the aim of eliciting enhanced antitumor immune responses. Here, we review recent advances in understanding of the fundamental biology of Tregs, and discuss the implications of these findings for current models of tumor-associated Treg biology. In particular, we discuss the context-dependent functional diversity of Tregs, the developmental origins of these cells, and the nature of the antigens that they recognize within the tumor environment. In addition, we highlight critical areas of focus for future research.

Striatal dopamine contributions to skilled motor learning.

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Impact of the COVID-19 pandemic on excess maternal deaths in Brazil: A two-year assessment.

BACKGROUND: Accurate estimates of the COVID-19 pandemic's indirect impacts are crucial, especially in low- and middle-income countries. This study aims to update estimates of excess maternal deaths in Brazil during the first two years of the COVID-19 pandemic. METHODS: This was an exploratory mixed ecological study using the counterfactual approach. The observed maternal deaths were gathered from the Mortality Information System (SIM) for the period between March 2015 and February 2022. Expected deaths from March 2020 to February 2022 were estimated using quasipoisson generalized additive models, considering quadrimester, age group, and their interaction as predictor variables. Analyses were performed in R version 4.1.2, RStudio, version 2023.03.1+446 and carried out with support from the "mgcv" and "plot_model" libraries. RESULTS: A total of 5,040 maternal deaths were reported, with varying excess mortality across regions and age groups, resulting in 69% excess maternal mortality throughout Brazil during the first two years of the pandemic. The Southeast region had 50% excess mortality throughout the first two years and 76% excess in the second year. The North region had 69% excess mortality, increasing in the second year, particularly among women aged 20-34. The Northeast region showed 80% excess mortality, with a significant increase in the second year, especially among women aged 35-49. The Central-West region had 75% excess mortality, higher in the second year and statistically significant among women aged 35-49. The South region showed 117% excess mortality, reaching 203% in the second year among women aged 20-34, but no excess mortality in the 10-19 age category. CONCLUSIONS: Over two years, Brazil saw a significant impact on maternal excess deaths, regardless of region and pandemic year. The highest peak occurred between March and June 2021, emphasizing the importance of timely and effective epidemic responses to prevent avoidable deaths and prepare for new crises.

Antibodies as drugs-a Keystone Symposia report.

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.