Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain - ABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) is an often long-lasting neurological condition that arises
frequently in cancer patients who receive broadly used chemotherapies such as taxanes. CIPN causes abnormal
pain and other symptoms that can limit chemotherapy dosage and significantly impact quality of life for years.
There are no drugs that prevent CIPN or treat it well. Duloxetine is the only clinically proven efficacious pain-
reducing agent, though it can cause significant side effects and its efficacy limited to a subset of patients. Opioids
are used off-label, but also carry serious side effects. Thus, there is a critical unmet need for drugs that safely
and effectively treat or prevent CIPN. Peripheral Cannabinoid 2 receptors (CB2) are a promising target for CIPN
treatment. CB2 is constitutively expressed on inflammatory immune cells and induced in peripheral neurons in
neuropathic conditions. Its activation has powerful neuroprotective, anti-inflammatory, and analgesic effects.
Rodent models of CIPN show that small molecule CB2 agonists alleviate neuropathic pain behavior, and when
administered prophylactically suppress CIPN both during dosing and for 100 days after. Several companies have
developed small molecule CB2 agonists that, unfortunately, are rapidly cleared, penetrate the blood-brain barrier
and/or have off-target effects (notably cognitive ones) mediated by the CB1 receptor. Abalone Bio used its
proprietary Functional Antibody Selection Technology (FAST) to isolate a selective CB2-activating nanobody
(VHH), which we converted into a VHH-Fc fusion lead antibody, ABt140, for in vivo studies. Phase I SBIR results
show that ABt140 rapidly and durably reversed allodynia in mice with CIPN. In this Phase II SBIR project,
Abalone Bio will first improve ABt140’s immunogenicity and manufacturability by rational engineering, and then
the FAST platform will be used to increase its potency to select durable agonists from millions of computationally-
designed variants. We will select 1 lead and at least 2 alternates using in vitro and in vivo assays. Using the
paclitaxel CIPN mouse model, we will assess the lead’s ability to prevent CIPN development, reduce in nerve
damage and inflammation, show no impairment of motor skills, and not affect chemotherapy’s anti-tumor
efficacy. Finally, we will determine the lead antibody’s half-life and tissue distribution in mice, and using blood
markers and organs appearance and weight, we will assess its toxicity at high doses. Successful completion of
these aims will de-risk the project sufficiently to advance Abalone’s antibody drug to IND-enabling studies and
eventually first in human trials for painful CIPN. Abalone’s drug may also have broad utility for other neuropathic
pains and inflammatory conditions.