Genmab (Denmark)

The brain is a highly metabolic organ primarily fueled by glucose, and it is well established that a decline in cerebral glucose metabolism accompanies neurodegenerative disease. Recent work using positron emission tomography (PET) has demonstrated that cerebral glucose metabolism is also reduced in healthy aging which commences as early as 20 years of age, driven almost exclusively by reductions in non-oxidative glucose metabolism, that is, aerobic glycolysis. Given the historical variability and assumptions in PET-based interpretations regarding cerebral glucose metabolism with aging, we aimed to establish whether a drop in global aerobic glycolysis is truly a component of healthy aging in adulthood using direct measures of carbohydrates and oxygen across the human brain via invasive cross-brain blood sampling. We accumulated resting data from 17 studies comprising 239 healthy adults aged 19-45 years and show that aerobic glycolysis remains stable during aging based on a regression analysis of the arteriovenous differences for oxygen, glucose, and lactate, and their resultant ratios (oxygen glucose/carbohydrate indices). The direct cross-brain data presented here indicate that declining brain aerobic glycolysis is not a feature of normal brain aging during early-mid adulthood.

An unmet need exists for patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose disease remains incurable. Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody, is approved for R/R FL and different types of R/R large B-cell lymphoma after ≥2 prior lines of therapy (pLOT) in the US, Europe, and Japan. Regional data are critical to contextualize global trial data. In the Japan-specific EPCORE NHL-3 trial (phase 1/2), 21 adults with R/R FL and ≥2 pLOT received subcutaneous epcoritamab (two step-up doses, then 48-mg full doses) until progression. Median follow-up was 21.2 months. Responses were frequent and deep (overall response rate, 95.2%; complete response rate, 76.2%), including in high-risk subgroups, as well as durable. Safety was manageable; cytokine release syndrome events had predictable timing and were mostly low grade, and no fatal treatment-emergent adverse events occurred. These results support epcoritamab as a new treatment option for Japanese patients with R/R FL.Clinical trial registration numbers: NCT04542824; JapicCTI-205408; jRCT2080225312

In lowlanders, high altitude (HA) acclimatization induces hemoconcentration by reducing plasma volume (PV) and increasing total hemoglobin mass (Hbmass). Conversely, Tibetan highlanders living at HA are reported to have a similar hemoglobin concentration ([Hb]) as lowlanders near sea level, and we investigated whether this reflects alterations in the PV or the Hbmass response to HA. Baseline assessment of PV and Hbmass was performed by carbon monoxide rebreathing at low altitudes (∼1,400 m) in Sherpas (an ethnic group of Tibetans living in Nepal) and native lowlanders. Participants then ascended to the Everest Base Camp (EBC) (5,400 m), where further measurements were performed after ∼2 days (EBC 1) and ∼6 wk (EBC 2). While on EBC 1 an increase in [Hb] was observed in lowlanders (P = 0.004) but not in Sherpas (P = 0.179), marked increases in [Hb] were observed in both groups on EBC 2 (P < 0.001). On EBC 1, Hbmass (Sherpas, P = 0.393; lowlanders, P = 0.123) and PV (Sherpas, P = 0.348; lowlanders, P = 0.172) were not different from baseline in either group, while circulating erythropoietin was increased in both groups (P < 0.001). On EBC 2, large increases in Hbmass and reductions in PV were observed along with elevated circulating erythropoietin in both groups (all P < 0.002). Neither the increases in erythropoietin on EBC 1 (P = 0.846) or EBC 2 (P = 0.564) nor the expansion of Hbmass (P = 0.771) or reduction in PV (P = 0.099) on EBC 2 differed between the groups. We conclude that the hematological response of Sherpas to extended exposure to very high altitudes does not fundamentally differ from that of native lowlanders.NEW & NOTEWORTHY We measured the hematological response to ∼6 wk exposure to an altitude of 5,400 m in Sherpa highland natives and Nepalese lowlanders. While the increase in hemoglobin concentration at high altitudes tended to be smaller in Sherpas than in lowlanders, the two groups experienced a similar reduction in plasma volume and increase in hemoglobin mass. We conclude that the hematological response of Sherpas to high-altitude exposure does not fundamentally differ from that of lowlanders.

ABSTRACT The naïve human antibody repertoire has theoretical access to an estimated > 1015 antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared (‘public’) CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.

Epcoritamab is a CD3xCD20 bispecific antibody (bsAb) that induces T‐cell–mediated cytotoxicity against CD20‐positive B cells. Target engagement and crosslinking of CD3 and CD20 (trimer formation) leads to activation and expansion of T cells and killing of malignant B cells. The primary objective of the dose‐escalation part of the phase I/II trial of epcoritamab was to determine the maximum tolerated dose, recommended phase II dose (RP2D), or both. For bsAbs, high target saturation can negatively affect trimer formation. The unique properties and mechanisms of action of bsAbs require novel pharmacokinetic (PK) modeling methods to predict clinical activity and inform RP2D selection. Traditional PK/pharmacodynamic (PD) modeling approaches are inappropriate because they may not adequately predict exposure–response relationships. We developed a semimechanistic, physiologically‐based PK/PD model to quantitatively describe biodistribution, trimer formation, and tumor response using preclinical, clinical PK, biomarker, tumor, and response data from the dose‐escalation part of the phase I/II trial. Clinical trial simulations were performed to predict trimer formation and tumor response in patients with diffuse large B‐cell lymphoma (DLBCL) or follicular lymphoma (FL). Model‐predicted trimer formation plateaued at doses of 48 to 96 mg. Simulation results suggest that the 48‐mg dose may achieve optimal response rates in DLBCL and FL. Exposure–safety analyses showed a flat relationship between epcoritamab exposure and risk of cytokine release syndrome in the dose range evaluated. This novel PK/PD modeling approach guided selection of 48 mg as the RP2D and provides a framework that may be applied to other CD3 bsAbs.