Eric Krauland

Peptide-mediated reduction of silver ions on engineered biological scaffolds.

Herein we report the spontaneous reduction of silver ions into nanostructures by yeast surface-displayed glutamic acid (E(6)) and aspartic acid (D(6)) peptides. Light spectroscopy and electron microscopy reveal that silver ions are photoreduced in the presence of the polycarboxylic acid-containing peptides and ambient light, with an increase in reduction capability of E(6) expressing yeast over D(6) yeast. The importance of tethering peptides to a biological scaffold was inferred by observing the reduced particle forming capacity of soluble peptides with respect to corresponding yeast-displayed peptides. This principle was further extended to the M13 virus for fabrication of crystalline silver nanowires. These insights into the spontaneous reduction of metal ions on biological scaffolds should help further the formation of novel nanomaterials in biological systems.

Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak

Profiling the antibody response to Ebola The recent Ebola virus outbreak in West Africa illustrates the need not only for a vaccine but for potential therapies, too. One promising therapy is monoclonal antibodies that target Ebolas membrane-anchored glycoprotein (GP). Bornholdt et al. isolated and characterized 349 antibodies from a survivor of the 2014 outbreak. A large fraction showed some neutralizing activity and several were quite potent. Structural analysis revealed an important site of vulnerability on the membrane stalk region of GP. Antibodies targeting this area were therapeutically effective in Ebola virus–infected mice. Science, this issue p. 1078 Antibodies from a survivor of the 2014 outbreak bind to the membrane proximal region of the Ebola virus glycoprotein. Antibodies targeting the Ebola virus surface glycoprotein (EBOV GP) are implicated in protection against lethal disease, but the characteristics of the human antibody response to EBOV GP remain poorly understood. We isolated and characterized 349 GP-specific monoclonal antibodies (mAbs) from the peripheral B cells of a convalescent donor who survived the 2014 EBOV Zaire outbreak. Remarkably, 77% of the mAbs neutralize live EBOV, and several mAbs exhibit unprecedented potency. Structures of selected mAbs in complex with GP reveal a site of vulnerability located in the GP stalk region proximal to the viral membrane. Neutralizing antibodies targeting this site show potent therapeutic efficacy against lethal EBOV challenge in mice. The results provide a framework for the design of new EBOV vaccine candidates and immunotherapies.

Biophysical properties of the clinical-stage antibody landscape

Significance In addition to binding to a desired target molecule, all antibody drugs must also meet a set of criteria regarding the feasibility of their manufacture, stability in storage, and absence of off-target stickiness. This suite of characteristics is often termed “developability.” We present here a comprehensive analysis of these properties for essentially the full set of antibody drugs that have been tested in phase-2 or -3 clinical trials, or are approved by the FDA. Surprisingly, many of the drugs or candidates in this set exhibit properties that indicate significant developability risks; however, the number of such red warning flags decreases with advancement toward approval. This reference dataset should help prioritize future drug candidates for development. Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of “developability.” Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.

Antibody Engineering and Therapeutics: December 8-12, 2013, Huntington Beach, CA

The 24th Antibody Engineering & Therapeutics meeting brought together a broad range of participants who were updated on the latest advances in antibody research and development. Organized by IBC Life Sciences, the gathering is the annual meeting of The Antibody Society, which serves as the scientific sponsor. Preconference workshops on 3D modeling and delineation of clonal lineages were featured, and the conference included sessions on a wide variety of topics relevant to researchers, including systems biology; antibody deep sequencing and repertoires; the effects of antibody gene variation and usage on antibody response; directed evolution; knowledge-based design; antibodies in a complex environment; polyreactive antibodies and polyspecificity; the interface between antibody therapy and cellular immunity in cancer; antibodies in cardiometabolic medicine; antibody pharmacokinetics, distribution and off-target toxicity; optimizing antibody formats for immunotherapy; polyclonals, oligoclonals and bispecifics; antibody discovery platforms; and antibody-drug conjugates.note: The views expressed herein are those of the authors and do not necessarily reflect the views of their respective employers. Speakers who wrote a summary of their own presentation are listed in the header for the relevant session. The majority of the other summaries in this report were based on PDFs of the presentations provided by speakers or on post-meeting input from the speakers. The authors thank all speakers who contributed to the report. When speakers could not contribute either the PDF or input, detailed summaries of their presentations were not prepared, although the names, affiliations and topics of all speakers were included in the report.