Treatments for prurigo nodularis
Described herein are treatments and preventions for prurigo nodularis (PN), antibodies and pharmaceutical compositions for use in the treatment or prevention of PN, and uses of an anti-IL-31RA antibody (e.g., nemolizumab) in the manufacture of a medicament for the treatment or prevention of PN. Also described herein are biomarkers of PN and methods of altering or improving these biomarkers via treatments with an antibody that binds to IL-31RA (e.g., nemolizumab).
1 . A method of treating prurigo nodularis (PN) in a subject, comprising administering to a subject with PN an anti-IL-31RA antibody (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more, wherein the subject differentially expresses at least three genes selected from KRT6C, DEFB4A, KRT16, LCE5A, AQP7, IL36A, IL36G, IL19, IL20, IL22, IL24, and IL26 compared to a reference level of expression for the at least three genes, wherein the reference level is the level of expression in a person that does not have PN, wherein the anti-IL-31RA antibody comprises a heavy chain variable region comprising a HCDR1 comprising SEQ ID NO: 8, a HCDR2 comprising SEQ ID NO: 9, and a HCDR3 comprising SEQ ID NO: 10, and a light chain variable region comprising a LCDR1 comprising SEQ ID NO: 12, a LCDR2 comprising SEQ ID NO: 13, and a LCDR3 comprising SEQ ID NO: 14.
2 . A method of normalizing differentially expressed genes (DEGs) in a subject with PN, comprising administering to a subject with prurigo nodularis (PN) an anti-IL-31RA antibody (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more, wherein the subject differentially expresses at least three genes selected from KRT6C, DEFB4A, KRT16, LCE5A, AQP7, IL36A, IL36G, IL19, IL20, IL22, IL24, and IL26 compared to a reference level of expression for the at least three genes and wherein administration of the anti-IL-31RA antibody normalizes the expression level of the at least one gene, wherein the reference level is the level of expression in a person that does not have PN, and wherein normalization is determined about 4 weeks after the initial dose of the anti-IL-31RA antibody, wherein the anti-IL-31RA antibody comprises a heavy chain variable region comprising a HCDR1 comprising SEQ ID NO: 8, a HCDR2 comprising SEQ ID NO: 9, and a HCDR3 comprising SEQ ID NO: 10, and a light chain variable region comprising a LCDR1 comprising SEQ ID NO: 12, a LCDR2 comprising SEQ ID NO: 13, and a LCDR3 comprising SEQ ID NO: 14.
3 . The method of claim 1 , wherein differential expression of the at least one gene was determined by RT-qPCR, RT-PCR, RNA-seq, Northern blotting, Serial Analysis of Gene Expression (SAGE), or DNA or RNA microarrays; or wherein differential expression of the at least one gene was determined at protein level by Western blotting, ELISA, surface plasmon resonance, or mass spectrometry.
4 . The method of claim 1 , wherein at least four of KRT6C, DEFB4A, KRT16, LCE5A, AQP7, IL36A, IL36G, IL19, IL20, IL22, IL24, and IL26 are differentially expressed.
5 . The method of claim 1 , wherein KRT6C, DEFB4A, KRT16, LCE5A, AQP7, IL36A, IL36G, IL19, IL20, IL22, IL24, and IL26 are differentially expressed.
6 . The method of claim 1 , wherein KRT6C, DEFB4A, and/or KRT16 are overexpressed compared to a reference level of expression.
7 . The method of claim 1 , wherein LCE5A and/or AQP7 are under expressed compared to a reference level of expression.
8 . The method of claim 1 , wherein the subject possesses a PN skin gene ontology selected from a cornified envelope, epidermal-cell differentiation, keratinization, peptidase regulatory activity, interleukin-4 and interleukin-13 signaling, interferon alpha/beta signaling, response to interferon gamma, IL23 pathway, and mitotic metaphase and anaphase.
9 . The method of claim 1 , wherein the anti-IL-31RA antibody is administered subcutaneously.
10 . The method of claim 1 , wherein the anti-IL-31RA antibody is administered at an initial dose of 60 mg of the anti-IL-31RA antibody followed by 60 mg once every 4 weeks if the subject weighs 90 kg or more.
11 . The method of claim 1 , wherein the anti-IL-31RA antibody is administered at an initial dose of 60 mg of the anti-IL-31RA antibody followed by 30 mg once every 4 weeks if the subject weighs less than 90 kg.
12 . The method of claim 1 , wherein pruritus scoring is improved in the subject.
13 . The method of claim 1 , wherein the HCDR1 consists of the amino acid sequence of SEQ ID NO: 8, the HCDR2 consists of the amino acid sequence of SEQ ID NO: 9, and the HCDR3 consists of the amino acid sequence of SEQ ID NO: 10, the LCDR1 consists of the amino acid sequence of SEQ ID NO: 12, the LCDR2 consists of the amino acid sequence of SEQ ID NO: 13, and the LCDR3 consists of the amino acid sequence of SEQ ID NO: 14.
14 . The method of claim 1 , wherein the anti-IL-31RA antibody is nemolizumab or a fragment or variant thereof.
15 . The method of claim 14 , wherein the anti-IL-31RA antibody is nemolizumab.
16 . A method of determining whether a subject with prurigo nodularis (PN) is responding to treatment with an anti-IL-31RA antibody, comprising detecting in a post-treatment sample obtained from a subject with PN about 4 weeks after administration of at least one dose of an anti-IL-31RA antibody the expression level of at least three differentially expressed genes (DEGs) selected from KRT6C, DEFB4A, KRT16, LCE5A, AQP7, IL36A, IL36G, IL19, IL20, IL22, IL24, and IL26, and comparing the expression level of the DEGs to a baseline level of expression, wherein the baseline level of gene expression is from a sample from the same individual before treatment was commenced; wherein the at least one dose is 60 mg of the anti-IL-31RA antibody, wherein the anti-IL-31RA antibody comprises a heavy chain variable region comprising a HCDR1 comprising SEQ ID NO: 8, a HCDR2 comprising SEQ ID NO: 9, and a HCDR3 comprising SEQ ID NO: 10, and a light chain variable region comprising a LCDR1 comprising SEQ ID NO: 12, a LCDR2 comprising SEQ ID NO: 13, and a LCDR3 comprising SEQ ID NO: 14, and wherein the anti-IL-31RA antibody is administered (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more.
17 . A method of treating prurigo nodularis (PN) in a subject, comprising administering to a subject with PN an anti-IL-31RA antibody (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more, wherein treatment with the anti-IL-31RA antibody results in at least one of the following relative to (i) a control plasma sample obtained from an individual or individuals without PN or (ii) a plasma sample obtained from the subject prior to administration of the anti-IL-31RA antibody:
(a) an inhibition of a STAT3 pathway;
(b) an inhibition of a STAT5b pathway;
(c) a downregulation of IL-6 or an IL-6 pathway;
(d) a downregulation of VEGF or a VEGF pathway;
(e) a decrease in TGFB1 pathway activation, or
(f) a combination thereof;
wherein the anti-IL-31RA antibody comprises a heavy chain variable region comprising a HCDR1 comprising SEQ ID NO: 8, a HCDR2 comprising SEQ ID NO: 9, and a HCDR3 comprising SEQ ID NO: 10, and a light chain variable region comprising a LCDR1 comprising SEQ ID NO: 12, a LCDR2 comprising SEQ ID NO: 13, and a LCDR3 comprising SEQ ID NO: 14, and wherein (a) the inhibition of a STAT3 pathway; (b) the inhibition of a STAT5b pathway; (c) the downregulation of IL-6 or an IL-6 pathway; (d) the downregulation of VEGF or a VEGF pathway; (e) the decrease in TGFB1 pathway activation, or (f) the combination thereof is assessed in a plasma sample from the subject taken after about 4 weeks after the initial dose of the anti-IL-31RA antibody.
18 . The method of claim 17 , wherein (a) the inhibition of a STAT3 pathway; (b) the inhibition of a STAT5b pathway; (c) the downregulation of IL-6 or an IL-6 pathway; (d) the downregulation of VEGF or a VEGF pathway; (e) the decrease in TGFB1 pathway activation, or (f) the combination thereof is determined by mass spectrometry performed on one or more biological sample(s) obtained from the subject.
19 . The method of claim 17 , wherein the subject exhibits at least two of (a) the inhibition of a STAT3 pathway; (b) the inhibition of a STAT5b pathway; (c) the downregulation of IL-6 or an IL-6 pathway; (d) the downregulation of VEGF or a VEGF pathway; and (e) the decrease in TGFB1 pathway activation.
20 . The method of claim 17 , wherein at least 4 weeks after administration of the anti-IL-31RA antibody, the subject additionally exhibits at least two of (a) a decrease in migration of leukocytes or cell movement of leukocytes; (b) an inhibition of a STAT3 pathway; (c) an inhibition of a STAT5b pathway; (d) a decrease in TGFB1 pathway activation.
21 . The method of claim 17 , wherein the anti-IL-31RA antibody is administered subcutaneously.
22 . The method of claim 17 , wherein the anti-IL-31RA antibody is administered at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more.
23 . The method of claim 17 , wherein the anti-IL-31RA antibody is administered at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more.
24 . The method of claim 17 , wherein pruritus scoring is improved in the subject.
25 . The method of claim 17 , wherein the anti-IL-31RA antibody is nemolizumab or a fragment or variant thereof.
26 . The method of claim 25 , wherein the anti-IL-31RA antibody is nemolizumab.
27 . A method of altering an immune response in a subject with PN, comprising administering to a subject with PN an anti-IL-31RA antibody (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more, wherein administration of the anti-IL-31RA antibody results in at least one of the following relative to (i) a control plasma sample obtained from an individual or individuals without PN or (ii) a plasma sample obtained from the subject prior to administration of the anti-IL-31RA antibody:
(a) an inhibition of a STAT3 pathway;
(b) an inhibition of a STAT5b pathway;
(c) a downregulation of IL-6 or an IL-6 pathway;
(d) a downregulation of VEGF or a VEGF pathway;
(e) a decrease in TGFB1 pathway activation, or
(f) a combination thereof;
wherein the anti-IL-31RA antibody comprises a heavy chain variable region comprising a HCDR1 comprising SEQ ID NO: 8, a HCDR2 comprising SEQ ID NO: 9, and a HCDR3 comprising SEQ ID NO: 10, and a light chain variable region comprising a LCDR1 comprising SEQ ID NO: 12, a LCDR2 comprising SEQ ID NO: 13, and a LCDR3 comprising SEQ ID NO: 14, and wherein (a) the inhibition of a STAT3 pathway; (b) the inhibition of a STAT5b pathway; (c) the downregulation of IL-6 or an IL-6 pathway; (d) the downregulation of VEGF or a VEGF pathway; (e) the decrease in TGFB1 pathway activation, or (f) the combination thereof is assessed in a plasma sample from the subject taken after about 4 weeks after the initial dose of the anti-IL-31RA antibody.
28 . A method of determining whether a subject with prurigo nodularis (PN) is responding to treatment with an anti-IL-31RA antibody, comprising detecting, using mass spectroscopy, in a post-treatment plasma sample obtained from a subject with PN that has been administered at least one dose of an anti-IL-31RA antibody the amount of at least one of:
(a) an inhibition of a STAT3 pathway;
(b) an inhibition of a STAT5b pathway;
(c) a downregulation of IL-6 or an IL-6 pathway;
(d) a downregulation of VEGF or a VEGF pathway;
(e) a decrease in TGFB1 pathway activation, or
(f) a combination thereof,
where the decrease or inhibition is measured relative to a baseline amount and the decrease or inhibition indicates responsiveness to treatment,
wherein the baseline amount was determined from a plasma sample obtained from the same subject before treatment was commenced, and
wherein treatment with the anti-IL-31RA antibody comprises administering the anti-IL-31RA antibody (i) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 30 mg once every 4 weeks if the subject weighs less than 90 kg, or (ii) at an initial dose of 60 mg of the anti-IL-31RA antibody followed by subsequent serial doses of 60 mg once every 4 weeks if the subject weighs 90 kg or more.