Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.
View Article and Find Full Text PDFLow-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in to form inactive head-to-tail dimers that slowly dissociate into an active monomer.
View Article and Find Full Text PDFPhys Rev Lett
November 2017
Using data from the ν-cleus detector, based on the surface of Earth, we place constraints on dark matter in the form of strongly interacting massive particles (SIMPs) which interact with nucleons via nuclear-scale cross sections. For large SIMP-nucleon cross sections, the sensitivity of traditional direct dark matter searches using underground experiments is limited by the energy loss experienced by SIMPs, due to scattering with the rock overburden and experimental shielding on their way to the detector apparatus. Hence, a surface-based experiment is ideal for a SIMP search, despite the much larger background resulting from the lack of shielding.
View Article and Find Full Text PDFPhys Rev Lett
November 2016
We quantify the amount of data needed in order to measure the size and position of the ^{8}B neutrino production region within the solar core, for experiments looking at elastic scattering between electrons and solar neutrinos. The directions of the electrons immediately after scattering are strongly correlated with the incident directions of the neutrinos; however, this is degraded significantly by the subsequent scattering of these electrons in the detector medium. We generate distributions of such electrons for different neutrino production profiles, and use a maximum likelihood analysis to make projections for future experimental sensitivity.
View Article and Find Full Text PDFWe consider the observation of diffuse halos of light around the discs of spiral galaxies, as a probe of the interaction cross section between dark matter (DM) and photons. Using the galaxy M101 as an example, we show that for a scattering cross section at the level of 10(-23)(m/GeV) cm(2) or greater dark matter in the halo will scatter light out from the more luminous center of the disc to larger radii, contributing to an effective increased surface brightness at the edges of the observed area on the sky. This allows us to set an upper limit on the DM-photon cross section using data from the Dragonfly instrument.
View Article and Find Full Text PDFPhys Rev Lett
August 2014
The DAMA/LIBRA experiment searches for evidence of dark matter scattering off nuclei. Data from DAMA show 9.2 σ evidence for an annual modulation, consistent with dark matter having a cross section around 2 × 10(-40) cm(2).
View Article and Find Full Text PDF7ND, a truncated version of the chemokine MCP-1/CCL2 lacking amino acids 2-8, is a potent antagonist of CCR2. In contrast to CCL2, 7ND is an obligate monomer. Similar to other chemokines, the in vivo half-life of 7ND is very short and its use as an antagonist in disease models is thus limited.
View Article and Find Full Text PDFAdnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹⁰Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹⁰Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23.
View Article and Find Full Text PDFBispecific antibodies and asymmetric Fc fusion proteins offer opportunities for important advances in therapeutics. Bivalent IgG depends upon in vivo dimerization of its heavy chains, mediated by homodimeric association of its C(H)3 domains. We have developed a heterodimeric Fc platform that supports the design of bispecific and asymmetric fusion proteins by devising strand-exchange engineered domain (SEED) C(H)3 heterodimers.
View Article and Find Full Text PDFHigher-affinity RNA aptamers to GTP are more informationally complex than lower-affinity aptamers. Analog binding studies have shown that the additional information needed to improve affinity does not specify more interactions with the ligand. In light of those observations, we would like to understand the structural characteristics that enable complex aptamers to bind their ligands with higher affinity.
View Article and Find Full Text PDFVery little is known about the distribution of functional DNA, RNA, and protein molecules in sequence space. The question of how the number and complexity of distinct solutions to a particular biochemical problem varies with activity is an important aspect of this general problem. Here we present a comparison of the structures and activities of eleven distinct GTP-binding RNAs (aptamers).
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2002
Aptamers, RNA sequences that bind to target ligands, are typically isolated by in vitro selection from RNA libraries containing completely random sequences. To see whether higher-affinity aptamers can be isolated from partially structured RNA libraries, we selected for aptamers that bind GTP, starting from a mixture of fully random and partially structured libraries. Because stem-loops are common motifs in previously characterized aptamers, we designed the partially structured library to contain a centrally located stable stem-loop.
View Article and Find Full Text PDFDuring the evolution of proteins the pressure to optimize biological activity is moderated by a need for efficient folding. For most proteins, this is accomplished through spontaneous folding to a thermodynamically stable and active native state. However, in the extracellular bacterial alpha-lytic protease (alphaLP) these two processes have become decoupled.
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