Characterization of the bispecific VHH antibody gefurulimab (ALXN1720) targeting complement component 5, and designed for low volume subcutaneous administration.

The bispecific antibody gefurulimab (also known as ALXN1720) was developed to provide patients with a subcutaneous treatment option for chronic disorders involving activation of the terminal complement pathway. Gefurulimab blocks the enzymatic cleavage of complement component 5 (C5) into the biologically active C5a and C5b fragments, which triggers activation of the terminal complement cascade. Heavy-chain variable region antigen-binding fragment (VHH) antibodies targeting C5 and human serum albumin (HSA) were isolated from llama immune-based libraries and humanized. Gefurulimab comprises an N-terminal albumin-binding VHH connected to a C-terminal C5-binding VHH via a flexible linker. The purified bispecific VHH antibody has the expected exact size by mass spectrometry and can be formulated at greater than 100 mg/mL. Gefurulimab binds tightly to human C5 and HSA with dissociation rate constants at pH 7.4 of 54 pM and 0.9 nM, respectively, and cross-reacts with C5 and serum albumin from cynomolgus monkeys. Gefurulimab can associate with C5 and albumin simultaneously, and potently inhibits the terminal complement activity from human serum initiated by any of the three complement pathways in Wieslab assays. Electron microscopy and X-ray crystallography revealed that the isolated C5-binding VHH recognizes the macroglobulin (MG) 4 and MG5 domains of the antigen and thereby is suggested to sterically prevent C5 binding to its activating convertase. Gefurulimab also inhibits complement activity supported by the rare C5 allelic variant featuring an R885H substitution in the MG7 domain. Taken together, these data suggest that gefurulimab may be a promising candidate for the potential treatment of complement-mediated disorders.

SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement factor Bb.

Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.

Two Phases Inside the Bose Condensation Dome of Yb_{2}Si_{2}O_{7}.

Recent experimental data on Bose-Einstein condensation of magnons in the spin-gap compound Yb_{2}Si_{2}O_{7} revealed an asymmetric Bose-Einstein condensation dome [G. Hester et al., Phys. Rev. Lett. 123, 027201 (2019)PRLTAO0031-900710.1103/PhysRevLett.123.027201]. We examine modifications to the Heisenberg model on a breathing honeycomb lattice, showing that this physics can be explained by competing anisotropic perturbations. We employ a gamut of analytical and numerical techniques to show that the anisotropy yields a field driven phase transition from a state with broken Ising symmetry to a phase that breaks no symmetries and crosses over to the polarized limit.

Knowledge, Awareness, and Attitude Towards Dementia Amongst Medical Undergraduate Students: Can a Sensitization Program Help?

BACKGROUND: Current undergraduate medical academic curriculum does not emphasize on evaluation and management of dementia. The knowledge and attitude of medical students towards patients with dementia in India has not been ascertained previously. OBJECTIVE: We aimed to assess the knowledge and attitude of final year medical students about dementia and Alzheimer's disease. We also aimed to assess if a dedicated sensitization cum teaching session by a group of interns doctors guided by a neurologist could help improve students' knowledge and awareness towards dementia or not. METHODS AND MATERIALS: 82 consenting final year medical students answered questionnaires of Alzheimer Disease Knowledge Scale (ADKS) and Dementia Attitude Scale (DAS) at a baseline level. A sensitization cum teaching session by intern doctors was conducted to enhance students' knowledge about dementia. A post sensitization reassessment of students was done to assess impact of the session. RESULTS: The ADKS score was 57% at baseline which was increased to 71% post sensitization program. The mean DAS score was 3.2 at baseline which was reported to be 3.4 after sensitization program. Students reported significant improvement in their knowledge level but did not show the same improvement in their attitude and comfort level in caring for dementia after the sensitization program. Students were still not comfortable dealing with patients with dementia. CONCLUSION: Medical students lack significant knowledge and training about dementia. Patient contact and practical training for basic assessment and care of dementia needs to be incorporated in the current academic curriculum. Dedicated sensitization sessions on dementia care can help improve the gap. Practical exposure to management of patients with dementia would be required to enhance the comfort level and attitude of students towards dementia.