Screening method for identifying anti-PACAP antibodies or antibody fragments suitable for use in treating or preventing PACAP-associated photophobia or light aversion

Patent metadata

Field	Value
Publication number	US-11993648-B2
Application number	US-202016953443-A
Country	US
Kind code	B2
Filing date	Nov 20, 2020
Priority date	Apr 16, 2015
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

This invention relates to methods of screening for anti-PACAP antibodies, or anti-PACAP receptor antibodies, and antigen binding fragments thereof, for potential use in treating or preventing PACAP-associated photophobia or light aversion, and therapeutic compositions containing and methods of using anti-PACAP antibodies, or anti-PACAP receptor antibodies, and antigen binding fragments thereof.

First claim

What is claimed is:

1. A method of screening for an antibody or antigen binding fragment suitable for use in treating or preventing Pituitary Adenylate Cyclase-Activating Peptide (PACAP)-associated photophobia or light aversion, or precluding the onset of PACAP-associated photophobia or light aversion, in a subject in need thereof,
which method comprises:
(i) providing at least one first test subject and at least one second test subject;
(ii) administering PACAP to the at least one first test subject and the at least one second test subject;
(iii) further administering to the at least one first test subject one or more anti-PACAP antibodies, or an antigen binding fragment of any of the foregoing, wherein said one or more antibodies or antigen binding fragments includes one comprising a variable heavy chain polypeptide having the heavy chain CDRs1-3 of SEQ ID NO: 44, 46 and 48 respectively; and a variable light chain polypeptide having the light chain CDRs1-3 of SEQ ID NO: 64, 66 and 68 respectively; or one comprising the variable heavy chain polypeptide of SEQ ID NO: 42 and the variable light chain polypeptide of SEQ ID NO: 62;
(iv) comparing the response of the at least one first test subject and the at least one second test subject to light; and
(v) based on this comparison, identifying one or more antibodies or antigen binding fragments thereof that yield a decreased light aversion or decreased photophobia in the at least one first test subject as compared with the at least one second test subject, thereby identifying an antibody or antigen binding fragment suitable for use in treating or preventing PACAP-associated photophobia or light aversion, or precluding the onset of PACAP-associated photophobia or light aversion in a subject in need thereof; or
which method comprises:
(i) providing at least one first test subject and at least one second test subject;
(ii) administering to the at least one first test subject one or more anti-PACAP antibodies, or an antigen binding fragment of any of the foregoing, wherein said one or more antibodies or antigen binding fragments thereof includes one comprising a variable heavy chain polypeptide having the heavy chain CDRs1-3 of SEQ ID NO: 44, 46 and 48 respectively; and a variable light chain polypeptide having the light chain CDRs1-3 of SEQ ID NO: 64, 66 and 68 respectively; or one comprising the variable heavy chain polypeptide of SEQ ID NO: 42 and the variable light chain polypeptide of SEQ ID NO: 62;
(iii) administering PACAP to the at least one first test subject and the at least one second test subject;
(iv) comparing the response of the at least one first test subject and the at least one second test subject to light; and
(v) based on this comparison, identifying antibodies or antigen binding fragments that yield decreased photophobia or decreased light aversion in the at least one first test subject as compared with the at least one second test subject, identifying an antibody or antigen binding fragment suitable for use in treating or preventing PACAP-associated photophobia or light aversion, or identifying an antibody or antigen binding fragment suitable for precluding the onset of PACAP-associated photophobia or light aversion, in a subject to be treated in need thereof.

2. The method of claim 1 , further comprising one or more of the following:
(i) further confirming in a human subject, the efficacy of the one or more antibodies or antigen binding fragments for inhibiting PACAP-associated photophobia or light aversion, or precluding the onset of PACAP-associated photophobia or light aversion;
(ii) the at least one first test subject and/or the at least one second test subject is a mammal;
(iii) the at least one first test subject and/or at least one second test subject is (i) a mouse, monkey, rabbit, human, rat, guinea pig, dog, or hamster, wherein optionally the monkey is a macaque, marmoset, tamarin, spider monkey, owl monkey, vervet monkey, squirrel monkey, or baboon; or (ii) a mouse, optionally a CD1 mouse;
(iv) the identified antibody or antigen binding fragment thereof specifically binds PACAP; and
(v) the method further comprises adapting the identified antibody or antigen binding fragment for use in treating a subject who suffers from one or more of migraine, hemiplegic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches, allergy-induced headaches, headache, or other migraine condition.

3. The method of claim 1 , wherein
(i) the subject to be treated has an ocular disorder associated with photophobia selected from one or more of achromatopsia, aniridia, photophobia caused by an anticholinergic drug, aphakia (absence of the lens of the eye), buphthalmos (abnormally narrow angle between the cornea and iris), cataracts, cone dystrophy, congenital abnormalities of the eye, viral conjunctivitis (“pink eye”), corneal abrasion, corneal dystrophy, corneal ulcer, disruption of the corneal epithelium, ectopia lentis, endophthalmitis, eye trauma caused by disease, injury, infection, optionally chalazion, episcleritis, glaucoma, keratoconus, optic nerve hypoplasia, hydrophthalmos, congenital glaucoma iritis, optic neuritis, pigment dispersion syndrome, pupillary dilation (naturally or chemically induced), retinal detachment, scarring of the cornea or sclera, and uveitis; or
(ii) the subject to be treated has a nervous-system-related or neurological condition associated with photophobia selected from one or more of autism spectrum disorders, chiari malformation, dyslexia, encephalitis including myalgic encephalomyelitis (chronic fatigue syndrome), meningitis, subarachnoid hemorrhage, tumor of the posterior cranial fossa, ankylosing spondylitis, albinism, ariboflavinosis, long term use of benzodiazepines, withdrawal from benzodiazepines, chemotherapy, chikungunya infection, cystinosis, Ehlers-Danlos syndrome, hangover, influenza infection, infectious mononucleosis, magnesium deficiency, mercury poisoning, migraine, rabies, and tyrosinemia type II (Richner-Hanhart syndrome); or
(iii) the subject to be treated has a photophobia-associated disorder selected from one or more of migraine (with or without aura), iritis, uveitis, meningitis, depression, bipolar disorder, cluster headache or another trigeminal autonomic cephalalgia or blepharospasm, depression, post-traumatic stress syndrome (PTSD) traumatic brain injury, and agoraphobia; or
(iv) the at least one first subject and/or the at least one second subject suffers from migraine headaches.

4. The method of claim 1 , wherein
(i) the one or more antibodies or antigen binding fragments thereof are for use in combination with another active agent for treating migraine, or are for use as a monotherapy;
(ii) the anti-PACAP antibody or fragment thereof comprises:
an immunoglobulin variable heavy chain having the CDR1 sequence of SEQ ID NO: 44; a CDR2 sequence of SEQ ID NO: 46; and a CDR3 sequence of SEQ ID NO: 48; and an immunoglobulin variable light chain having the CDR1 sequence of SEQ ID NO: 64; a CDR2 sequence of SEQ ID NO: 66; and a CDR3 sequence of SEQ ID NO: 68; and/or

(iii) the antibody or fragment thereof is a humanized antibody or fragment thereof;
(iv) the antibody or fragment thereof is a chimeric antibody or fragment thereof;
(v) the antibody or fragment thereof comprises a single chain antibody or fragment thereof;
(vi) the chimeric antibody or fragment thereof comprises a human Fc, optionally a human Fc is derived from IgG1, IgG2, IgG3, or IgG4;
(vii) the anti-PACAP antibody or fragment thereof binds to PACAP with a binding affinity (K D ) of less than or equal to 5×10 −5 M, 10 −5 M, 5×10 −6 M, 10 −6 M, 5×10 −7 M, 10 −7 M, 5×10 −8 M, 10 −8 M, 5×10 −

Assignees

• H Lundbeck As
• The Univ Of Iowa Research Foundation
• The Univ Of Lowa Research Foundation

Inventors

• Kuburas Adisa
• Mason Bianca
• Sowers Levi P
• Russo Andrew F
• Loomis Maria-Cristina
• Garcia-Martinez Leon F
• Dutzar Benjamin H
• Allison Daniel S
• Hendrix Katherine Lee
• Ojala Ethan W
• Fan Pei
• Smith Jeffrey T L
• Latham John A
• Karasek Charlie
• Mulligan Jenny
• Scalley-Kim Michelle
• Stewart Erica
• Rubin Vanessa Lisbeth
• Billgren Jens J

Classifications

• A61K49/0008

  Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure · CPC title

• A61K49/0004

  Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions · CPC title

• C07K16/4241

  against anti-human or anti-animal Ig · CPC title

• A61K39/39566

  against immunoglobulins, e.g. anti-idiotypic antibodies · CPC title

• G01N33/74

  involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors} · CPC title