Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

SummaryTherapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain Chroniclife disrupting painsuch as allodynia from chemotherapy induced peripheral neuropathyCIPNis difficult to manageIn this Phase I SBIRAbalone Bio proposes to develop a first in class specific CBagonist antibody that is BOTH an effective and safe analgesic against CIPN as well as a co therapy to enable opioid based pain management without developing toleranceCIPN occurs in andgtof chemotherapy patients treated with taxanesand in various degrees for other therapiesTaxane CIPN is an untreated chronic condition that involves various degrees of allodyniafor which there is no demonstrated relief by any drugOpioidswhile frequently prescribedare not clinically proven to effectively treat CIPNOn the contraryheavy usage can lead to tolerance to opioidsand in turn opioid use disordersOUDsEfforts to develop drugs aimed at novel pain targetsincluding the peripheral cannabinoid receptor CBhave so far yielded lackluster performance in clinical trialsSmall molecule CBagonists have been shown to reduce allodynia and reduce opioid tolerance in an established mouse model of chronic chemotherapy induced peripheral neuropathyCIPNBut small molecule CBagonists have drawbacksthey are rapidly clearedundesirably stimulate brain CBreceptorsand cross react with CBreceptors in the periphery and in the brainAbalone s CBagonist antibody will be BOTH highly specific and thus will not cross react with CBreceptors in the periphery avoid CBreceptorsand will also avoid the stimulation of brain CBreceptors by being naturally restricted to peripheral tissues by the blood brain barrierBy using our proprietary FAST platformwe isolated three single chain camelid VHH domain antibodies hitsa k ananobodiesconsistent with agonist activity for human CBIn this Phase I workthe first aim will be to identify in vitro at leasttherapeutic format VHH Fcs with with Kd andltnM for human CBKd andltnM for mouse CBand ECof AC inhibition or ERK activation andltnM for human and mouse CBTo do thiswe ll find suitable VHHs using FASTconvert them to FC fusions and produce protein for assaysWe ll measure hit function using mammalian cell based assays and measure hit affinityapparent KDusing flow cytometry on live cellsFor antibody leads meeting criteria the second aim will be to assess in vivo effect on allodynia and opioid tolerance and identify at leastVHH Fc that either or both reduces allodynia toof baseline levels and extends morphine efficacy at dayof morphine treatment toof dayWe ll use a broadly accepted CBLJ mouse model of CIPN and study their pharcokyneticsadvancing all non toxic leads to pharmacodynamic studies to determine dosing regime for subthreshold analgesiaThen we ll measure prevention of opioid tolerance and CBspecificityThe impact of this work could be very broad with our CBagonist antibody drug becoming a class defining non opioid analgesic and co therapy that prevents the development of opioid tolerance Project Narrative The proposed project will develop drugs to treat pain due to chemotherapyThe proposed drugs are expected to be an effective and safe treatment to manage painas well as a co therapy to enable opioid based treatment without developing a toleranceThe proposed drugs will enable safer pain managementand help reduce opioid addictionone of the most pressing health problems facing the country today