Antibody engineering &amp; therapeutics, the annual meeting of the antibody society December 7–10, 2015, San Diego, CA, USA

Pauthner, Matthias; Yeung, Jenny; Ullman, Chris; Bakker, Joost M.; Wurch, Thierry; Reichert, Janice M.; Lund-Johansen, Fridtjof; Bradbury, Andrew; Carter, Paul J.; Melis, Joost P.M.

doi:10.1080/19420862.2016.1153211

Cited by 8 publications

(10 citation statements)

References 51 publications

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“…Recently, a single antibody (CrossMab 2+2 ) combined at the site of Fc binding both IL-17 and TNFα was reported as a therapeutic opportunity in RA using human fibroblast-like synoviocytes (FLS) in vitro and arthritic mice in vivo [ 60 , 61 ]. In addition, another single antibody (ABT-122) binding both IL-17 and TNFα at the site of Fab was reported showing effectiveness and safety in RA therapy [ 62 ]. In addition, based on the marketed anti-TNF antibody adalimumab, Silacci et al generated the bispecific TNF/IL-17-binding FynomAb COVA322 [ 60 ].…”

Section: Possible Implications For Novel Therapiesmentioning

confidence: 99%

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

Kotake

Yago

Kobashigawa

et al. 2017

JCM

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Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., “nonclassic Th1 cells”), which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells) is elevated and that levels of interferon-γ (IFNγ)+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies.

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Section: Possible Implications For Novel Therapiesmentioning

confidence: 99%

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

Kotake

Yago

Kobashigawa

et al. 2017

JCM

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“…Thus, the next generation of immunoconjugates will necessitate alterations to the antibody and/or the cytotoxic moieties and will likely be dependent on target receptor densities, valency of the constructs, efficiency of receptor mediated uptake and subcellular delivery of warheads to their compartment of action. To this end, some progress has ensued, with the engineering of bispecific antibodies and protein translocation domains flanked with cleavable adapters to allow efficient internalization and transport of lethal warheads into the cytosol, respectively [ 242 ]. Additionally, the introduction of supercomputing tools to study enzyme-substrate interactions [ 33 , 159 ], and modelling simulations that measure cellular processing parameters including binding, internalization, trafficking, and drug release/accumulation will undoubtedly foster the development of next-generation highly efficient apoptosis-inducing molecules [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies

et al. 2020

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The epidermal growth factor receptor (EGFR) has been recognized as an important therapeutic target in oncology. It is commonly overexpressed in a variety of solid tumors and is critically involved in cell survival, proliferation, metastasis, and angiogenesis. This multi-dimensional role of EGFR in the progression and aggressiveness of cancer, has evolved from conventional to more targeted therapeutic approaches. With the advent of hybridoma technology and phage display techniques, the first anti-EGFR monoclonal antibodies (mAbs) (Cetuximab and Panitumumab) were developed. Due to major limitations including host immune reactions and poor tumor penetration, these antibodies were modified and used as guiding mechanisms for the specific delivery of readily available chemotherapeutic agents or plants/bacterial toxins, giving rise to antibody-drug conjugates (ADCs) and immunotoxins (ITs), respectively. Continued refinement of ITs led to deimmunization strategies based on depletion of B and T-cell epitopes or substitution of non-human toxins leading to a growing repertoire of human enzymes capable of inducing cell death. Similarly, the modification of classical ADCs has resulted in the first, fully recombinant versions. In this review, we discuss significant advancements in EGFR-targeting immunoconjugates, including ITs and recombinant photoactivable ADCs, which serve as a blueprint for further developments in the evolving domain of cancer immunotherapy.

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“…The enhanced therapeutic efficacy of MM-151 has been attributed to binding of novel epitopes located on EGFR domain I and domain III that are distinct from those of cetuximab and panitumumab 2 . Another example is HT-19, an anti-human epidermal growth factor receptor (HER)2 antibody being developed as an antibody-drug conjugate, which binds an epitope distinct from that of pertuzumab and trastuzumab, 3 and indeed from other known domain I 17 and domain III 18 HER2 epitopes. A third example is the broadly neutralizing, cross-reactive antibody against α-hemolysin and 4 additional leukocidins, with superior effectiveness in combating S. aureus infections compared to antibodies targeting α-hemolysin alone 8,19 .…”

Section: Discussionmentioning

confidence: 99%

Broad epitope coverage of a human in vitro antibody library

Sivasubramanian

Estep

Lynaugh

et al. 2016

mAbs

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Successful discovery of therapeutic antibodies hinges on the identification of appropriate affinity binders targeting a diversity of molecular epitopes presented by the antigen. Antibody campaigns that yield such broad “epitope coverage” increase the likelihood of identifying candidates with the desired biological functions. Accordingly, epitope binning assays are employed in the early discovery stages to partition antibodies into epitope families or “bins” and prioritize leads for further characterization and optimization. The collaborative program described here, which used hen egg white lysozyme (HEL) as a model antigen, combined 3 key capabilities: 1) access to a diverse panel of antibodies selected from a human in vitro antibody library; 2) application of state-of-the-art high-throughput epitope binning; and 3) analysis and interpretation of the epitope binning data with reference to an exhaustive set of published antibody:HEL co-crystal structures. Binning experiments on a large merged panel of antibodies containing clones from the library and the literature revealed that the inferred epitopes for the library clones overlapped with, and extended beyond, the known structural epitopes. Our analysis revealed that nearly the entire solvent-exposed surface of HEL is antigenic, as has been proposed for protein antigens in general. The data further demonstrated that synthetic antibody repertoires provide as wide epitope coverage as those obtained from animal immunizations. The work highlights molecular insights contributed by increasingly higher-throughput binning methods and their broad utility to guide the discovery of therapeutic antibodies representing a diverse set of functional epitopes.

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Antibody engineering & therapeutics, the annual meeting of the antibody society December 7–10, 2015, San Diego, CA, USA

Cited by 8 publications

References 51 publications

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis

Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies

Broad epitope coverage of a human in vitro antibody library

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