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Generation of a CCL2-CGRP bispecific neutralizing antibody to treat chronic post-traumatic headache

Award Number: R61NS146000
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Generation of a CCL2-CGRP bispecific neutralizing antibody to treat chronic post-traumatic headache - Project Summary/Abstract Post-traumatic headache (PTH) is the most common and persistent consequence of mild traumatic brain injury (mTBI), affecting millions of Americans every year. Despite its prevalence and disabling impact, there is no approved treatment specifically for chronic PTH. Many patients use/misuse opioids, which heightens the risk of addiction and overdose death, underscoring the urgent need for safe and effective non-opioid therapies. Although both clinical and animal studies implicates both neuropeptide CGRP (calcitonin gene-related peptide) and chemokine C-C motif ligand 2 (CCL2) signaling in the pathogenesis of chronic PTH, inhibiting either pathway alone only protects mice against some PTH triggers and not the others. Remarkably, our preliminary data demonstrate that dual blockade of CGRP and CCL2 signaling fully prevented chronic PTH- related behavioral sensitization in mice across multiple clinically relevant PTH triggers, establishing a strong scientific premise for a combinatorial approach. We propose to develop a first-in-class bispecific antibody (BsAb) that simultaneously neutralizes CCL2 and CGRP as a novel non-opioid treatment for chronic PTH. In the R61 phase, we will generate chimeric neutralizing Abs against human CGRP and CCL2. Single- chain variable fragment (scFv) phage display libraries will be constructed with RNA from splenocytes of immunized rabbits. Customized panning will be conducted to select phages that show strong and selective antigen binding at pH 7.4 but weaker binding at pH 5.8, aiming to facilitate antigen clearance. After converting scFvs to chimeric Abs, we will screen for Abs that bind to human and mouse antigens with high affinity, and robustly neutralize their functions. After confirming that the combination treatment is superior to single Ab administration in a mouse model of chronic PTH, we will select one anti-CGRP and two anti-CCL2 chimeric Abs that bind to distinct epitopes on human CCL2 for the R33 phase. In the R33 phase, we will first humanize the top chimeric Abs to retain all desired features. Next, we will engineer multiple BsAb configurations with the anti-CCL2 arm in biparatopic format to further enhance antigen clearance. Top BsAb will be selected based on the binding affinity, neutralizing ability to human and mouse antigens, and drug-like properties. Last, initial in vivo pharmacokinetic study will be performed to assess the blood half-life, the levels in dura and trigeminal ganglion tissues and the efficiency of BsAb-antigen complex clearance. The therapeutic efficacy of the top BsAb will be assessed in the mouse model of chronic PTH to see if it matches or exceeds the efficacy of the combination of humanized Abs and outperforms monotherapies. Upon completion of the project, we will obtain a humanized CCL2-CGRP neutralizing BsAb with enhanced antigen clearance and validated preclinical efficacy, ready for advancing to the Blueprint Neurotherapeutics Network for Biologic-based Drugs. All in all, this project will deliver a novel, non-opioid therapeutic strategy for chronic PTH, addressing a major public health burden and transforming care for patients with mTBI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $816,375 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2026	NEW	$816,375
														Subtotal = $816,375

Grand Total All Awards = $816,375

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Generation of a CCL2-CGRP bispecific neutralizing antibody to treat chronic post-traumatic headache

Award Number: R61NS146000

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/24/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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