Lokivetmab and Cytokine Transcriptome

Question 1

Does lokivetmab affect lesions, pruritus, or both?

Answer 1

Pruritus only, no significant difference in macroscopic or microscopic lesion scores

Question 2

What cytokines are upregulated after 24 hours in lokivetab treated dogs?

Answer 2

IL33, IL13, CCL17 (ligand for CCR4), and IL9
(also IL6 and CCL22 after 24hr but no longer at 96hr)
(IL9 and CCL22 not confirmed by qRT-PCR)
(also IL1B but only at 24hr and IL18 and IL10 only at 96hr)

Question 3

What are some cytokines that may be down regulated after lokivetmab (but no statistical significance)?

Answer 3

IFNg, CXCL10, CXCL11, TSLP

Question 4

What differences were found in gene transcription for skin barrier after lokivetmab?

Answer 4

Minimal, downregulation of S100A9 and S100A12 but only at 48hr

Question 5

Is IL31 essential for the induction of acute allergic skin inflammation?

Answer 5

No, no effect on lesions

Question 6

What cytokines and chemokines does IL31 induce release of in vitro?

Answer 6

Proinflammatory cytokines IL1B and IL6 and AD-related chemokines CXCL1, CXCL8, CCL2, CCL18 in vitro from eosinophils, esp when co-cultured with keratinocytes

Question 7

IL31 stimulates what to be released by human monocyte-derived DCs?

Answer 7

Proinflammatory cytokines TNFa, IL6, CXCL8, CCL2, CCL5, CCL22

Question 8

IL31 increased the gene expression of what cytokines and chemokines from normal human epidermal keratinocytes in vitro?

Answer 8

CXCL1, CCL1, CCL4, CCL17, CCL19, CCL22, CCL23, IL20, and IL24

Question 9

What canine cytokine-encoding genes were upregulated in lokivetmab treated dogs?

Answer 9

IL36G and IL37 upregulated

Question 10

What canine cytokine-encoding genes were downregulated in lokivetmab treated dogs?

Answer 10

CXCL8, IL9, and CCL17

Question 11

What are possible targets for inhibition that might complement lokivetmab due to active gene expression levels and upregulation compared to baseline in lokivetmab treated dogs?

Answer 11

IL33, IL13, CCL17, and IL9 (also IL6 and CCL22); up regulation of mRNA or protein expression of IL33, IL13, and CCL17 has been reported in skin or serum of AD dogs

Question 12

What cytokines are produced at a very early stage of AD acute flare induction (before Th2 cells produce IL31)?

Answer 12

IL33, CCL17, IL6, and CCL22

Question 13

What is the difference in TEWL in lokivetmab treated dogs between acute and chronic use?

Answer 13

TEWL is significantly reduced at some body sites after 3 months, but no difference is seen at 96hr

Question 14

In vitro studies in people have shown that IL31 has what effect on the expression of some proteins associated with the physical skin barrier (filaggrin, filaggrin-processing enzymes, desmogleins, desmocollins and corneodesmosin)?

Answer 14

Down regulates the expression in a dose-dependent manner

Question 15

IL31-deficient mice exposed chronically to HDM showed significantly _________ numbers of dermal-infiltrating INFg, IL4, IL13 producing cells compared to wild-type mice.

Answer 15

Increased: indicating that IL31 might function as a negative regulator of TH1 and TH2 inflammation in chronic AD, explaining some flares while dogs are treated with lokivetmab

Question 16

What major canine AD-relevant cytokine groups does IL31 directly affect?

Answer 16

None

Question 17

What cytokines are identified as participating in acute flares of AD skin inflammation in dogs receiving IL31-blocking treatment with lokivetmab?

Answer 17

IL33, IL13, CCL17, and IL9, potentially IL6 and CCL22; inhibiting these cytokines or their receptors, especially proactively, may help prevent canine AD flares

Question 18

What is significant about the highest numbers of DEGs (differentially expressed genes) in the lokivetmab group being seen at 48 hrs?

Answer 18

Consistent with the highest median IL31 mRNA expression