Engineered interleukin-6-derived cytokines recruit artificial receptor complexes and disclose CNTF signaling via the OSMR.

Ciliary neurotrophic factor (CNTF) activates cells via the non-signaling α-receptor CNTF receptor (CNTFR) and the two signaling ß-receptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). The CNTF derivate, Axokine, was protective against obesity and insulin resistance, but clinical development was halted by the emergence of CNTF antibodies. The chimeric cytokine IC7 used the framework of interleukin (IL-)6 with the LIFR-binding site from CNTF to activate cells via IL-6R:gp130:LIFR complexes. Similar to CNTF/Axokine, IC7 protected mice from obesity and insulin resistance. Here, we developed CNTF-independent chimeras that specifically target the IL-6R:gp130:LIFR complex. In GIL-6 and GIO-6, we transferred the LIFR binding site from LIF or OSM to IL-6, respectively. While GIO-6 signals via gp130:IL-6R:LIFR and gp130:IL-6R:OSMR complexes, GIL-6 selectively activates the IL-6R:gp130:LIFR receptor complex. By re-evaluation of IC7 and CNTF, we discovered the Oncostatin M receptor (OSMR) as an alternative non-canonical high-affinity receptor leading to IL-6R:OSMR:gp130 and CNTFR:OSMR:gp130 receptor complexes, respectively. The discovery of OSMR as an alternative high-affinity receptor for IC7 and CNTF designates GIL-6 as the first truly selective IL-6R:gp130:LIFR cytokine, whereas GIO-6 is a CNTF-free alternative for IC7.

Bispecific soluble cytokine receptor-nanobody fusions inhibit Interleukin (IL-)6 trans-signaling and IL-12/23 or tumor necrosis factor (TNF) signaling.

At least 0.5% of people in the Western world develop inflammatory bowel disease (IBD). While antibodies that block tumor necrosis factor (TNF) α and Interleukin (IL-)23 have been approved for the treatment of IBD, IL-6 antibodies failed in the phase II clinical trial due to non-tolerable side effects. However, two clinical phase II studies suggest that inhibiting IL-6/soluble IL-6R (sIL-6R)-induced trans-signaling via the cytokine receptor gp130 benefit IBD patients with fewer adverse events. Here we develop inhibitors targeting a combination of IL-6/sIL-6R and TNF or IL-12/IL-23 signaling, named cs130-TNFVHHFc and cs130-IL-12/23VHHFc. Surface plasmon resonance experiments showed that recombinant cs130-TNFVHHFc and cs130-IL-12/23VHHFc bind with high affinity to IL-6/sIL-6R complexes and human TNFα (hTNFα) or IL-12/IL-23, respectively. Immunoprecipitation experiments have verified the higher ordered complex formation of the inhibitors with IL-6/sIL-6R and IL-12. We demonstrated that cs130-TNFVHHFc and cs130-IL-12/23VHHFc block IL-6/sIL-6R trans-signaling-induced proliferation and STAT3 phosphorylation of Ba/F3-gp130 cells, as well as hTNFα- or IL-23-induced signaling, respectively. In conclusion, cs130-TNFVHHFc and cs130-IL-12/23VHHFc represent a class of dimeric and bispecific chimeric cytokine inhibitors that consist of a soluble cytokine receptor fused to anti-cytokine nanobodies.

Why so few Nobel Prizes for cancer researchers? An analysis of Nobel Prize nominations for German physicians with a focus on Ernst von Leyden and Karl Heinrich Bauer.

PURPOSE: To date, 11 scientists have received the Nobel Prize for discoveries directly related to cancer research. This article provides an overview of cancer researchers nominated for the Nobel Prize from 1901 to 1960 with a focus on Ernst von Leyden (1832-1910), the founder of this journal, and Karl Heinrich Bauer (1890-1978). METHODS: We collected nominations and evaluations in the archive of the Nobel committee of physiology or medicine in Sweden to identify research trends and to analyse oncology in a Nobel Prize context. RESULTS: We found a total of 54 nominations citing work on cancer as motivation for 11 candidates based in Germany from 1901 to 1953. In the 1930s, the US became the leading nation of cancer research in a Nobel context with nominees like Harvey Cushing (1869-1939) and George N. Papanicolaou (1883-1962). DISCUSSION: The will of Alfred Nobel stipulates that Nobel laureates should have "conferred the greatest benefit to mankind". Why were then so few cancer researchers recognized with the Nobel medal from 1901 to 1960? Our analysis of the Nobel dossiers points at multiple reasons: (1) Many of the proposed cancer researchers were surgeons, and surgery has a weak track record in a Nobel context; (2) several scholars were put forward for clinical work and not for basic research (historically, the Nobel committee has favoured basic researchers); (3) the scientists were usually not nominated for a single discovery, but rather for a wide range of different achievements.

Babinski, Bektherev, Cerletti, Head, and Hitzig: European Neurologists Nominated for the Nobel Prize 1901-1950.

INTRODUCTION: This article provides for the first time an overview of the most often nominated European neurologists for the Nobel Prize, who never received the award. It sheds light on candidates from France, Germany, Italy, Russia, and the UK during the first half of the 20th century. The aim is to highlight the candidates in the field of neurology, to discuss key arguments in the nomination letters, and to raise questions about research trends and hotspots in European neurology 1901-1950. METHODS: Using the Nobel nomination database which contains >5,000 nominations in the prize category physiology or medicine from 1901 to the early 1950s, we listed European neurologists who were nominated more than once during this time period. We then collected nomination letters and jury reports of the prime candidates in the archive of the Nobel Committee for physiology or medicine in Sweden to explore nomination networks and motives. RESULTS: We pinpointed scholars like Joseph Babinski, Vladimir Bektherev, Sir Henry Head, Eduard Hitzig, and Ugo Cerletti. The nomination motives were diverse, ranging from "lifetime" achievements and textbooks to singular (eponymous) discoveries. Issues of scientific priority disputes were central in most nomination letters. CONCLUSION: Nobel Prize nominations constitute a lens through which credit and recognition around major contributions in neurology during the 20th century can be examined. They are unique sources that enable the reconstruction of both research trends in the field and the reputation of individual neurologists.