Povetacicept, an Enhanced Dual APRIL/BAFF Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell-Related Autoimmune Diseases.

Objective: Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high-affinity APRIL/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors.

Methods: A variant of TACI-Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN-303).

The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.

Despite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4-CD80/CD86 interactions.

Assessment of left anterior descending artery stenosis of intermediate severity by fractional flow reserve, instantaneous wave-free ratio and non-invasive coronary flow reserve.

Unlabelled: Assessment of the functional significance of left anterior descending coronary artery (LAD) stenosis of intermediate severity is challenging and often based on fractional flow reserve (FFR). The instantaneous wave-free ratio (IFR), a new vasodilator-free index of coronary stenosis severity, and non-invasive coronary flow reserve (CFR) by transthoracic Doppler echocardiography are also potentially useful. A direct comparison of FFR, IFR, and non-invasive CFR has never been performed.

Assessment of left anterior descending artery stenosis of intermediate severity by fractional flow reserve, instantaneous wave-free ratio, and non-invasive coronary flow reserve.

To test the usefulness of non-invasive coronary flow reserve (CFR) by transthoracic Doppler echocardiography by comparison to invasive fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR), a new vasodilator-free index of coronary stenosis severity, in patients with left anterior descending artery (LAD) stenosis of intermediate severity (IS) and stable coronary artery disease. 94 consecutive patients (mean age 68 ± 10 years) with angiographic LAD stenosis of IS (50-70 % diameter stenosis), were prospectively studied. IFR was calculated as a trans-lesion pressure ratio during the wave-free period in diastole; FFR as distal pressure divided by mean aortic pressure during maximal hyperemia (using 180 μg intracoronary adenosine); and CFR as hyperemic peak LAD flow velocity divided by baseline flow velocity using intravenous adenosine (140 μg/kg/min over 2 min).

Vstm3 is a member of the CD28 family and an important modulator of T-cell function.

Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs.