The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity.

BACKGROUND: Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. METHODS: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. RESULTS: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. CONCLUSIONS: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.

A 6-minute sub-maximal run test to predict VO2 max.

Maximal oxygen uptake ([Formula: see text] max) is a key indicator to assess health as well as sports performance. Currently, maximal exercise testing is the most accurate measure of maximal aerobic power, since submaximal approaches are still imprecise. In this paper, we propose a new method to predict [Formula: see text] max from a submaximal, low intensity, test in sports men and women. 182 males and 108 females from the High Performance Center of Pontevedra (Spain), aged 10-46 years old, with a [Formula: see text] max between 30.1 and 81.2 mL·min-1·kg-1, completed a maximal incremental test to volitional exhaustion. The test began at a speed of 6 km·h-1 and increased by 0.25 km·h-1 every 15 seconds. Using the data gathered during the first 6 minutes of the test, two different regression models were adjusted using functional data analysis and a traditional linear regression model with scalar covariates. The functional regression model obtained the best results, adjusted r2 = 0.845 and RMSE = 2.8 mL·min-1·kg-1, but the linear regression model also obtained a good fit, adjusted r2 = 0.798 and RMSE = 3.5 mL·min-1·kg-1. Both methods are more accurate than classical submaximal tests, although oxygen consumption needs to be measured during the test.

Depot- and ethnic-specific differences in the relationship between adipose tissue inflammation and insulin sensitivity.

OBJECTIVE: It is unclear whether there are differences in inflammatory gene expression between abdominal and gluteal subcutaneous adipose tissue (SAT), and between black and white women. We therefore tested the hypotheses that SAT inflammatory gene expression is greater in the abdominal compared to the gluteal depot, and SAT inflammatory gene expression is associated with differential insulin sensitivity (S(I) ) in black and white women. DESIGN AND METHODS: S(I) (frequently sampled intravenous glucose tolerance test) and abdominal SAT and gluteal SAT gene expression levels of 13 inflammatory genes were measured in normal-weight (BMI 18-25 kg/m²) and obese (BMI >30 kg/m²) black (n = 30) and white (n = 26) South African women. RESULTS: Black women had higher abdominal and gluteal SAT expression of CCL2, CD68, TNF-α and CSF-1 compared to white women (P < 0·01). Multivariate analysis showed that inflammatory gene expression in the white women explained 56·8% of the variance in S(I) (P < 0·005), compared to 20·9% in black women (P = 0·30). Gluteal SAT had lower expression of adiponectin, but higher expression of inflammatory cytokines, macrophage markers and leptin than abdominal SAT depots (P < 0·05). CONCLUSIONS: Black South African women had higher inflammatory gene expression levels than white women; however, the relationship between AT inflammation and S(I) was stronger in white compared to black women. Further research is required to explore other factors affecting S(I) in black populations. Contrary to our original hypothesis, gluteal SAT had a greater inflammatory gene expression profile than abdominal SAT depots. The protective nature of gluteo-femoral fat therefore requires further investigation.

Avoiding futile damage control laparotomy.

BACKGROUND: The age of a patient, lowest pre-operative pH and lowest core temperature are significant predictors of mortality in patients undergoing damage control surgery (DCS). An equation had previously been devised based on these three variables, which could predict which patients would die despite undergoing DCS (100% positive predictive value, 25% sensitivity). The aim of this study was to validate this equation by testing it on a different cohort of patients undergoing DCS. PATIENTS AND METHODS: A retrospective validation study of patients who underwent DCS over a four-year period (1998-2001) was undertaken. The lowest pre-operative pH, lowest pre-operative core temperature and age were recorded and the equation was used to predict which patients were "unsalvageable". This was then compared to the true outcomes of these patients. RESULTS: A total of 73 case notes were analysed for the period 1998-2001. The equation predicted that eight patients were unsalvageable. All eight patients died (100% positive predictive value), despite DCS being utilised. A further 25 of the rest of the "potentially salvageable" patients also died (24% sensitivity). When data of the original study (2002-2004) was combined with the current study data, the cohort totalled 145 patients, of whom 53 died (37%). Thirteen of these would have been predicted as unsalvageable with a 100% positive predictive value, had the equation been used during this time. CONCLUSION: Both the positive predictive value and sensitivity of the equation remain consistent. When resources are overwhelmed by multiple casualties, this equation could prove useful in identifying patients in whom surgery may be futile, allowing surgical triage to be directed in a more efficient manner.