Combining somatic mutations present in different<i>in vivo</i>affinity-matured antibodies isolated from immunized<i>Lama glama</i>yields ultra-potent antibody therapeutics

Klarenbeek, A.; Blanchetot, Christophe; Schragel, Georg; Sadi, Ava; Ongenae, Nico; Hemrika, Wieger; Wijdenes, John; Spinelli, S.; Desmyter, Aline; Cambillau, Christian; Hultberg, Anna; Kretz-Rommel, Anke; Dreier, Torsten; Haard, Hans J. W. de; Roovers, Rob C.

doi:10.1093/protein/gzw003

Cited by 12 publications

(16 citation statements)

References 46 publications

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“…It has been postulated that only in the hexameric quaternary structure is IL-6 able to function properly [ 41 , 42 ]. Several artificial receptors have been tested against IL-6, IL-6R, and gp-130 [ 18 ], and some of those entered and passed clinical trials [ 7 , 8 , 9 , 10 , 18 , 28 , 43 , 44 ]. All of these receptors show high affinity to the ligand and have specific inhibitory abilities.…”

Section: Methodsmentioning

confidence: 99%

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Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors

2020

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Cytokines are a family of proteins which play a major role in the regulation of the immune system and the development of several diseases, from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being developed to improve therapy and diagnosis, as well as to produce inhibitory drugs and biosensors for a rapid, minimally invasive, and effective detection. In this regard, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of IL-6 cytokine receptors, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an idealized experimental setup.

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Section: Methodsmentioning

confidence: 99%

“…SOMAmers are effective against many ligands and also proteins usually considered challenging [ 39 , 49 ]. In particular, SOMAmer SL1025 [ 43 , 50 ] binds with high affinity (K D = 0.2 nM) to human IL-6 protein and blocks the binding with IL-6R [ 51 ]. It is efficacious against rheumatoid arthritis in animal trials [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors

2020

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“…Immunization with recombinant IL-6, phage Fab library construction, selection, screenings, chain shuffling, production, and purification of antibodies have been previously described ( 22 ).…”

Section: Methodsmentioning

confidence: 99%

“…SPR was performed using a Biacore 3000 and low density IL-6 coating (∼75–100 resonance units) on a CM5-Chip (GE Healthcare) to determine the k off of Fab mutants produced in periplasmic fractions as previously described ( 22 ). k off was measured over a 10-min washing period (30 μl/min) and evaluated using the BIAevaluation software.…”

Section: Methodsmentioning

confidence: 99%

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Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies

Blanchetot

Jonge

Desmyter

et al. 2016

Journal of Biological Chemistry

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Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. Here we describe the crystal structures of the complexes of IL-6 with two Fabs derived from conventional camelid antibodies that antagonize the interaction between the cytokine and its receptor. The x-ray structures of these complexes provide insights into the mechanism of neutralization by the two antibodies and explain the very high potency of one of the antibodies. It effectively competes for binding to the cytokine with IL-6 receptor (IL-6R) by using side chains of two CDR residues filling the site I cavities of IL-6, thus mimicking the interactions of Phe229 and Phe279 of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe279. Mutation of this HCDR3 Trp residue into any other residue except Tyr or Phe significantly weakens binding of the antibody to IL-6, as was also observed for IL-6R mutants of Phe279. In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe279, whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe229.

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A Mesenchymal‐Epithelial Transition Factor‐Agonistic Antibody Accelerates Cirrhotic Liver Regeneration and Improves Mouse Survival Following Partial Hepatectomy

Que

et al. 2021

Liver Transpl

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Small‐for‐size syndrome (SFSS) is a common complication following partial liver transplantation and extended hepatectomy. SFSS is characterized by postoperative liver dysfunction caused by insufficient regenerative capacity and portal hyperperfusion and is more frequent in patients with preexisting liver disease. We explored the effect of the Mesenchymal‐epithelial transition factor (MET)‐agonistic antibody 71D6 on liver regeneration and functional recovery in a mouse model of SFSS. Male C57/BL6 mice were exposed to repeated carbon tetrachloride injections for 10 weeks and then randomized into 2 arms receiving 3 mg/kg 71D6 or a control immunoglobulin G (IgG). At 2 days after the randomization, the mice were subjected to 70% hepatectomy. Mouse survival was recorded up to 28 days after hepatectomy. Satellite animals were euthanized at different time points to analyze liver regeneration, fibrosis, and inflammation. Serum 71D6 administration significantly decreased mouse mortality consequent to insufficient regeneration of the cirrhotic liver. Analysis of liver specimens in satellite animals revealed that 71D6 promoted powerful activation of the extracellular signal‐regulated kinase pathway and accelerated liver regeneration, characterized by increased liver‐to‐body weight, augmented mitotic index, and higher serum albumin levels. Moreover, 71D6 accelerated the resolution of hepatic fibrosis as measured by picrosirius red, desmin, and α–smooth muscle actin staining, and suppressed liver infiltration by macrophages as measured by CD68 and F4/80 staining. Analysis of gene expression by reverse‐transcription polymerase chain reaction confirmed that 71D6 administration suppressed the expression of key profibrotic genes, including platelet‐derived growth factor, tissue inhibitor of metalloproteinase 3, and transforming growth factor‐β1, and of key proinflammatory genes, including tumor necrosis factor‐α, interleukin‐1β, chemokine (C‐C motif) ligand 3, and chemokine (C‐C motif) ligand 5. These results suggest that activating the MET pathway via an hepatocyte growth factor–mimetic antibody may be beneficial in patients with SFSS and possibly other types of acute and chronic liver disorders.

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Combining somatic mutations present in differentin vivoaffinity-matured antibodies isolated from immunizedLama glamayields ultra-potent antibody therapeutics

Cited by 12 publications

References 46 publications

Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors

Biosensing Cytokine IL-6: A Comparative Analysis of Natural and Synthetic Receptors

Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies

A Mesenchymal‐Epithelial Transition Factor‐Agonistic Antibody Accelerates Cirrhotic Liver Regeneration and Improves Mouse Survival Following Partial Hepatectomy

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