Measurements of Arterial Occlusion Pressure Using Hand-Held Devices.

ABSTRACT: Vehrs, PR, Reynolds, S, Allen, J, Barrett, R, Blazzard, C, Burbank, T, Hart, H, Kasper, N, Lacey, R, Lopez, D, and Fellingham, GW. Measurements of arterial occlusion pressure using hand-held devices. J Strength Cond Res 38(5): 873-880, 2024-Arterial occlusion pressure (AOP) of the brachial artery was measured simultaneously using Doppler ultrasound (US), a hand-held Doppler (HHDOP), and a pulse oximeter (PO) in the dominant (DOM) and nondominant (NDOM) arms of males ( n = 21) and females ( n = 23) using continuous (CONT) and incremental (INCR) cuff inflation protocols. A mixed-model analysis of variance revealed significant ( p < 0.05) overall main effects between AOP measured using a CONT (115.7 ± 10.9) or INCR (115.0 ± 11.5) cuff inflation protocol; between AOP measured using US (116.3 ± 11.2), HHDOP (115.4 ± 11.2), and PO (114.4 ± 11.2); and between males (120.7 ± 10.6) and females (110.5 ± 9.4). The small overall difference (1.81 ± 3.3) between US and PO measures of AOP was significant ( p < 0.05), but the differences between US and HHDOP and between HHDOP and PO measures of AOP were not significant. There were no overall differences in AOP between the DOM and NDOM arms. Trial-to-trial variance in US measurements of AOP was not significant when using either cuff inflation protocol but was significant when using HHDOP and PO and a CONT cuff inflation protocol. Bland-Altman plots revealed reasonable limits of agreement for both HHDOP and PO measures of AOP. The small differences in US, HHDOP, and PO measurements of AOP when using CONT or INCR cuff inflation protocols are of minimal practical importance. The choice of cuff inflation protocol is one of personal preference. Hand-held Doppler of PO can be used to assess AOP before using blood flow restriction during exercise.

Tissue optimization strategies for high-quality ex vivo diffusion imaging.

Ex vivo diffusion imaging can be used to study healthy and pathological tissue microstructure in the rodent brain with high resolution, providing a link between in vivo MRI and ex vivo microscopy techniques. Major challenges for the successful acquisition of ex vivo diffusion imaging data however are changes in the relaxivity and diffusivity of brain tissue following perfusion fixation. In this study we address this question by examining the combined effects of tissue preparation factors that influence signal-to-noise ratio (SNR) and consequently image quality, including fixative concentration, contrast agent concentration and tissue rehydration time. We present an optimization strategy combining these factors to manipulate the T 1 and T 2 of fixed tissue and maximize SNR efficiency. We apply this strategy in the rat brain, for a diffusion-weighted spin echo protocol with TE = 27 ms on a 9.4 T scanner with a 39 mm volume coil and 660 mT/m 114 mm gradient insert. We used a reduced fixative concentration of 2% paraformaldehyde (PFA), rehydration time more than 20 days, 15 mM Gd-DTPA in perfusate and TR 250 ms. This resulted in a doubling of SNR and an increase in SNR per unit time of 135% in cortical grey matter and 88% in white matter compared with 4% PFA and no contrast agent. This improved SNR efficiency enabled the acquisition of excellent-quality high-resolution (78 µ m isotropic voxel size) diffusion data with b = 4000 s/mm 2 , 30 diffusion directions and a field of view of 40 × 13 × 18 mm3 in less than 4 days. It was also possible to achieve comparable data quality for a standard resolution (150 µ m) diffusion dataset in 2 1 4 h. In conclusion, the tissue optimization strategy presented here may be used to improve SNR, increase spatial resolution and/or allow faster acquisitions in preclinical ex vivo diffusion MRI experiments.

Differences in Frontal Network Anatomy Across Primate Species.

The frontal lobe is central to distinctive aspects of human cognition and behavior. Some comparative studies link this to a larger frontal cortex and even larger frontal white matter in humans compared with other primates, yet others dispute these findings. The discrepancies between studies could be explained by limitations of the methods used to quantify volume differences across species, especially when applied to white matter connections. In this study, we used a novel tractography approach to demonstrate that frontal lobe networks, extending within and beyond the frontal lobes, occupy 66% of total brain white matter in humans and 48% in three monkey species: vervets (Chlorocebus aethiops), rhesus macaque (Macaca mulatta) and cynomolgus macaque (Macaca fascicularis), all male. The simian-human differences in proportional frontal tract volume were significant for projection, commissural, and both intralobar and interlobar association tracts. Among the long association tracts, the greatest difference was found for tracts involved in motor planning, auditory memory, top-down control of sensory information, and visuospatial attention, with no significant differences in frontal limbic tracts important for emotional processing and social behaviour. In addition, we found that a nonfrontal tract, the anterior commissure, had a smaller volume fraction in humans, suggesting that the disproportionally large volume of human frontal lobe connections is accompanied by a reduction in the proportion of some nonfrontal connections. These findings support a hypothesis of an overall rearrangement of brain connections during human evolution.SIGNIFICANCE STATEMENT Tractography is a unique tool to map white matter connections in the brains of different species, including humans. This study shows that humans have a greater proportion of frontal lobe connections compared with monkeys, when normalized by total brain white matter volume. In particular, tracts associated with language and higher cognitive functions are disproportionally larger in humans compared with monkeys, whereas other tracts associated with emotional processing are either the same or disproportionally smaller. This supports the hypothesis that the emergence of higher cognitive functions in humans is associated with increased extended frontal connectivity, allowing human brains more efficient cross talk between frontal and other high-order associative areas of the temporal, parietal, and occipital lobes.

British Association of Urological Surgeons (BAUS) and Nurses (BAUN) consensus document: management of the complications of long-term indwelling catheters.

OBJECTIVE: To look at best evidence and expert opinion to provide advice in the form of a consensus statement lead by Female, Neurological and Urodynamic Urology (FNUU) section of the British Association of Urological Surgeons (BAUS) in conjunction with the British Association of Urological Nurses (BAUN). METHODS: Initially a literature search was performed with incorporation of aspects of the existing guidance and further informed by UK best practice by core members of the group. The document then underwent reviews by the FNUU Executive Committee members, the BAUN executive committee, a separate experienced urologist and presented at the BAUS annual meeting 2020 to ensure wider feedback was incorporated in the document. RESULTS: Complications of long-term indwelling catheters include catheter-associated urinary tract infections (CAUTI), purple urine bag syndrome, catheter blockages, bladder spasms (causing pain and urinary leakage), loss of bladder capacity, urethral erosion ("catheter hypospadias")/dilatation of bladder outlet and chronic inflammation (metaplasia and cancer risk). CONCLUSIONS: We have provided a list of recommendations and a troubleshooting table to help with the management of the complications of long term catheters.

Design and characterization of Zweimab and Doppelmab, high affinity dual antagonistic anti-TSLP/IL13 bispecific antibodies.

Patients with severe Th2 type asthma often have a steroid resistant phenotype and are prone to acute exacerbations. Current novel therapies have only marginal therapeutic effects. One of the hypotheses for lack of major efficacy in most patients is targeting only one redundant pathway leaving others active. Hence, we have designed and developed novel highly potent bispecific anti-TSLP/IL13 antibodies called Zweimabs (monovalent bispecific) and Doppelmabs (bivalent bispecific) that concurrently inhibits the signaling by these two cytokines.

Efficient Qualitative and Quantitative Determination of Antigen-induced Immune Responses.

To determine the effectiveness of immunization strategies used in therapeutic antibody or vaccine development, it is critical to assess the quality of immunization-induced polyclonal antibody responses. Here, we developed a workflow that uses sensitive methods to quantitatively and qualitatively assess immune responses against foreign antigens with regard to antibody binding affinity and epitope diversity. The application of such detailed assessments throughout an immunization campaign can significantly reduce the resources required to generate highly specific antibodies. Our workflow consists of the following two steps: 1) the use of surface plasmon resonance to quantify antigen-specific antibodies and evaluate their apparent binding affinities, and 2) the recovery of serum IgGs using an automated small scale purification system, followed by the determination of their epitope diversity using hydrogen deuterium exchange coupled with mass spectrometry. We showed that these methods were sensitive enough to detect antigen-specific IgGs in the nanogram/µl range and that they provided information for differentiating the antibody responses of the various immunized animals that could not be obtained by conventional methods. We also showed that this workflow can guide the selection of an animal that produces high affinity antibodies with a desired epitope coverage profile, resulting in the generation of potential therapeutic monoclonal antibody clones with desirable functional profiles. We postulate that this workflow will be an important tool in the development of effective vaccines to combat the highly sophisticated evasion mechanisms of pathogens.

FISH identifies a KAT6A/CREBBP fusion caused by a cryptic insertional t(8;16) in a case of spontaneously remitting congenital acute myeloid leukemia with a normal karyotype.

Cytogenetics can inform risk stratification in pediatric acute myeloid leukemia (AML). We describe the first case of a newborn with leukemia cutis found to have AML harboring a cryptic insertional t(8;16)(p11.2;p13.3) with associated KAT6A/CREBBP fusion identified exclusively by fluorescence in situ hybridization (FISH). Expectant management resulted in spontaneous leukemia resolution. The identification of t(8;16)(p11.2;p13.3) may serve as a biomarker for spontaneous remission in congenital AML. FISH for this translocation is warranted in congenital AML with a normal karyotype, and patients with KAT6A/CREBBP fusion should be conservatively managed. While 50% of spontaneously remitting congenital AML with t(8;16)(p11.2;p13.3) may recur, high salvage rates are attained with standard therapy.

Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics.

The acquisition of reliable kinetic parameters for the characterization of biomolecular interactions is an important component of the drug discovery and development process. While several benchmark studies have explored the variability of kinetic rate constants obtained from multiple laboratories and biosensors, a direct comparison of these instruments' performance has not been undertaken, and systematic factors contributing to data variability from these systems have not been discussed. To address these questions, a panel of ten high-affinity monoclonal antibodies was simultaneously evaluated for their binding kinetics against the same antigen on four biosensor platforms: GE Healthcare's Biacore T100, Bio-Rad's ProteOn XPR36, ForteBio's Octet RED384, and Wasatch Microfluidics's IBIS MX96. We compared the strengths and weaknesses of these systems and found that despite certain inherent systematic limitations in instrumentation, the rank orders of both the association and dissociation rate constants were highly correlated between these instruments. Our results also revealed a trade-off between data reliability and sample throughput. Biacore T100, followed by ProteOn XPR36, exhibited excellent data quality and consistency, whereas Octet RED384 and IBIS MX96 demonstrated high flexibility and throughput with compromises in data accuracy and reproducibility. Our results support the need for a "fit-for-purpose" approach in instrument selection for biosensor studies.

Short-term heat waves have long-term consequences for parents and offspring in stickleback.

Extreme temperature events, such as heat waves, can have lasting effects on the behavior, physiology, and reproductive success of organisms. Here, we examine the impact of short-term exposure to a simulated heat wave on condition, parental care, and reproductive success in a population of threespine stickleback (Gasterosteus aculeatus), a small fish with exclusive paternal care, currently experiencing regular heat waves. Males were either exposed to a simulated heat wave (23 °C) for 5 d or held at an ideal temperature (18 °C). Following this 5-d treatment, all males were transferred to 18 °C, where they completed a full parenting cycle. Offspring were raised at 18 °C. We found that while mass and body condition were unaffected in males exposed to a heat wave, cortisol responses were dampened across the nesting cycle compared to control males. In addition, heat wave males had longer latency for eggs to hatch, lower hatching success, and showed lower levels of parental care behavior compared to control males. Offspring of heat wave males had lower body condition, affecting swimming performance. Altogether, our results highlight the long-term impact that even short-term events can have on reproductive success, parental behavior, and subsequent generations, providing insight into population responses to rapid environmental change.

Multiple isoforms of the translation initiation factor eIF4GII are generated via use of alternative promoters, splice sites and a non-canonical initiation codon.

During the initiation stage of eukaryotic mRNA translation, the eIF4G (eukaryotic initiation factor 4G) proteins act as an aggregation point for recruiting the small ribosomal subunit to an mRNA. We previously used RNAi (RNA interference) to reduce expression of endogenous eIF4GI proteins, resulting in reduced protein synthesis rates and alterations in the morphology of cells. Expression of EIF4G1 cDNAs, encoding different isoforms (f-a) which arise through selection of alternative initiation codons, rescued translation to different extents. Furthermore, overexpression of the eIF4GII paralogue in the eIF4GI-knockdown background was unable to restore translation to the same extent as eIF4GIf/e isoforms, suggesting that translation events governed by this protein are different. In the present study we show that multiple isoforms of eIF4GII exist in mammalian cells, arising from multiple promoters and alternative splicing events, and have identified a non-canonical CUG initiation codon which extends the eIF4GII N-terminus. We further show that the rescue of translation in eIF4GI/eIF4GII double-knockdown cells by our novel isoforms of eIF4GII is as robust as that observed with either eIF4GIf or eIF4GIe, and more than that observed with the original eIF4GII. As the novel eIF4GII sequence diverges from eIF4GI, these data suggest that the eIF4GII N-terminus plays an alternative role in initiation factor assembly.

Relating Factors and Trends in Hearing Device Adoption Rates to Opportunities for Hearing Health Care Providers.

As with many professions, audiology is continuing to evolve. More specifically in terms of hearing device technology, we see evolution in remote accessibility to providers, public knowledge of devices, and services provided by hearing care professionals. Each of these topics plays a role in an individual's decision to pursue any sort of hearing care services. Given the variety of new devices soon coming to the market (over-the-counter devices), it is important for the audiologist to understand patient motivators and how they have a great impact on both the practice of audiology as well as the patient's overall satisfaction. The goal of this article is to investigate the MarkeTrak 2022 data to determine the trends in adoption and use of hearing aids as well as examine predictive factors that can be used to better understand hearing aid adoption.

Real-Ear-to-Coupler Difference: Physical and Perceptual Differences.

PURPOSE: The real-ear-to-coupler difference (RECD) is a recommended measure for accurate hearing aid fittings, especially for pediatric populations. However, for adults, many clinicians question whether it is necessary. METHOD: Hearing aids were fit on two groups of 85 older adults seen at a Veterans Administration audiology clinic. One group was fit using RECD measurements, whereas the second group was fit with population-based average RECD values. The two groups had similar pure-tone hearing thresholds. RESULTS: Like previous studies, there was little difference between the measured RECD for the right and left ears among the participants. Although the majority of the measured RECDs were within 1 SD of the mean, approximately 20% of those measured were outside of the normal range. It also was found that all participants produced lower (improved) Hearing Handicap Inventory for Elderly-Screening (HHIE-S) scores from pre- to postfitting, thus suggesting a reduction in self-perceived hearing handicap. CONCLUSIONS: Despite having similar prefitting HHIE-S scores, those participants who had their hearing aids fit using measured RECD values had lower postfitting scores than the group that was fit with average RECD values. Furthermore, there was a significant difference between the groups on several questions of the International Outcome Inventory-Hearing Aids, suggesting that there was higher satisfaction with the fittings based on the custom RECD rather than the fittings based on the average RECD. This study demonstrated that, in addition to performing verification using real-ear measurements, accurate conversion of dB HL to dB SPL using personalized RECD likely improved hearing aid satisfaction.

Sema3A Antibody BI-X Prevents Cell Permeability and Cytoskeletal Collapse in HRMECs and Increases Tip Cell Density in Mouse Oxygen-Induced Retinopathy.

Purpose: Semaphorin 3A (Sema3A) is an axonal guidance molecule that inhibits angiogenesis by vasorepulsion and blocks revascularization in the ischemic retina. BI-X is an intravitreal anti-Sema3A agent under clinical investigation in patients with proliferative diabetic retinopathy (PDR) and diabetic macular ischemia (DMI). Methods: Surface plasmon resonance was used to determine binding affinity of BI-X to human and murine Sema3A. In vitro, human retinal microvascular endothelial cells (HRMECs) were used to assess effects of BI-X on cell permeability and cytoskeletal collapse induced by Sema3A. In vivo, intravitreal BI-X or an anti-trinitrophenol control antibody was administered in both eyes in mice with oxygen-induced retinopathy (OIR). Retinal flat mounts were prepared, and avascular area and tip cell density were determined using confocal laser-scanning microscopy. Results: Dissociation constants for BI-X binding to human and murine Sema3A were 29 pM and 27 pM, respectively. In vitro, BI-X prevented HRMEC permeability and cytoskeletal collapse induced by Sema3A. In vivo, BI-X increased tip cell density by 33% (P < 0.001) and reduced avascular area by 12% (not significant). A significant negative correlation was evident between avascular area and tip cell density (r2 = 0.4205, P < 0.0001). Conclusions: BI-X binds to human Sema3A with picomolar affinity and prevents cell permeability and cytoskeletal collapse in HRMECs. BI-X also enhances revascularization in mice with OIR. Translational Relevance: BI-X is a potent inhibitor of human Sema3A that improves revascularization in a murine model of OIR; BI-X is currently being investigated in patients with laser-treated PDR and DMI.

Distinct immune stimulatory effects of anti-human VISTA antibodies are determined by Fc-receptor interaction.

VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.

Effect of the ADCC-Modulating Mutations and the Selection of Human IgG Isotypes on Physicochemical Properties of Fc.

Monoclonal antibodies, particularly IgGs and Ig-based molecules, are a well-established and growing class of biotherapeutic drugs. In order to improve efficacy, potency and pharmacokinetics of these therapeutic drugs, pharmaceutical industries have investigated significantly in engineering fragment crystallizable (Fc) domain of these drugs to optimize the interactions of these drugs and Fc gamma receptors (FcγRs) in recent ten years. The biological function of the therapeutics with the antibody-dependent cellular cytotoxicity (ADCC) enhanced double mutation (S239D/I332E) of isotype IgG1, the ADCC reduced double mutation (L234A/L235A) of isotype IgG1, and ADCC reduced isotype IgG4 has been well understood. However, limited information regarding the effect of these mutations or isotype difference on physicochemical properties (PCP), developability, and manufacturability of therapeutics bearing these different Fc regions is available. In this report, we systematically characterize the effects of the mutations and IgG4 isotype on conformation stability, colloidal stability, solubility, and storage stability at accelerated conditions in two buffer systems using six Fc variants. Our results provide a basis for selecting appropriate Fc region during development of IgG or Ig-based therapeutics and predicting effect of the mutations on CMC development process.

Case Study Comparison: Limitations in Telehealth Relating to Poverty and Family Support.

Telehealth appointments have grown in popularity due to the COVID-19 global pandemic. Three cases presented in this article show several different perspectives where telehealth was utilized. For the first patient, appointments were successfully completed via telehealth; however, the patient's family opted to continue with an unsecure internet connection at a local laundromat. For the second patient, a stable internet connection could not be obtained in his home, thus making telehealth appointments unavailable. The caregiver of this patient ended up driving to the clinic to have adjustments made in person. For the third patient, telehealth appointments were unavailable due to unstable internet connections as well as difficulty setting up video interpreting services. These cases highlight the idea that telehealth can be incredibly beneficial, when used correctly. For some, the option to attend appointments virtually gives them access to specialists that otherwise may not be available. For other patients, aspects such as access to smart devices and steady internet access must be considered to ensure a successful connection. The hope is that this article sheds light on some of the potential setbacks that can come from the use of telehealth appointments in a practice and provides discussion regarding for whom telehealth may be appropriate, even in pediatric patients. After reading this article, readers should be able to discuss ways in which there could be solutions for these barriers that may prevent some patients from utilizing these types of virtual appointments.

Protocol for a hybrid type 2 cluster randomized trial of trauma-focused cognitive behavioral therapy and a pragmatic individual-level implementation strategy.

BACKGROUND: More than two-thirds of youth experience trauma during childhood, and up to 1 in 5 of these youth develops posttraumatic stress symptoms that significantly impair their functioning. Although trauma-focused cognitive behavior therapy (TF-CBT) has a strong evidence base, it is rarely adopted, delivered with adequate fidelity, or evaluated in the most common setting where youth access mental health services-schools. Given that individual behavior change is ultimately required for successful implementation, even when organizational factors are firmly in place, focusing on individual-level processes represents a potentially parsimonious approach. Beliefs and Attitudes for Successful Implementation in Schools (BASIS) is a pragmatic, motivationally focused multifaceted strategy that augments training and consultation and is designed to target precise mechanisms of behavior change to produce enhanced implementation and youth clinical outcomes. This study protocol describes a hybrid type 2 effectiveness-implementation trial designed to concurrently evaluate the main effects, mediators, and moderators of both the BASIS implementation strategy on implementation outcomes and TF-CBT on youth mental health outcomes. METHODS: Using a cluster randomized controlled design, this trial will assign school-based mental health (SMH) clinicians and schools to one of three study arms: (a) enhanced treatment-as-usual (TAU), (b) attention control plus TF-CBT, or (c) BASIS+TF-CBT. With a proposed sample of 120 SMH clinicians who will each recruit 4-6 youth with a history of trauma (480 children), this project will gather data across 12 different time points to address two project aims. Aim 1 will evaluate, relative to an enhanced TAU condition, the effects of TF-CBT on identified mechanisms of change, youth mental health outcomes, and intervention costs and cost-effectiveness. Aim 2 will compare the effects of BASIS against an attention control plus TF-CBT condition on theoretical mechanisms of clinician behavior change and implementation outcomes, as well as examine costs and cost-effectiveness. DISCUSSION: This study will generate critical knowledge about the effectiveness and cost-effectiveness of BASIS-a pragmatic, theory-driven, and generalizable implementation strategy designed to enhance motivation-to increase the yield of evidence-based practice training and consultation, as well as the effectiveness of TF-CBT in a novel service setting. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT04451161 . Registered on June 30, 2020.

An optimally designed anti-human CD40 antibody with potent B cell suppression for the treatment of autoimmune diseases.

Antibodies targeting the CD40-CD40L pathway have great potential for treating autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), and inflammatory bowel diseases (IBD). However, in addition to the known difficulty in generating a purely antagonistic CD40 antibody, the presence of CD40 and CD40L on platelets creates additional unique challenges for the safety, target coverage, and clearance of antibodies targeting this pathway. Previously described therapeutic antibodies targeting this pathway have various shortcomings, and the full therapeutic potential of this axis has yet to be realized. Herein, we describe the generation and characterization of BI 655064, a novel, purely antagonistic anti-CD40 antibody that potently neutralizes CD40-CD40L-dependent B-cell stimulation without evidence of impacting platelet functions. This uniquely optimized antibody targeting a highly challenging pathway was obtained by applying stringent functional and biophysical criteria during the lead selection process. BI 655064 has favorable target-mediated drug disposition (TMDD)-saturation pharmacokinetics, consistent with that of a high-quality therapeutic monoclonal antibody.

Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist.

Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).