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Engineering a unique antibody for patients with RA

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI147697-01A1
Agency Tracking Number: R41AI147697
Amount: $600,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA19-270
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-04-16
Award End Date (Contract End Date): 2022-03-31
Small Business Information
San Diego, CA 92121-1318
United States
DUNS: 078689678
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (858) 352-0911
Business Contact
Phone: (858) 352-6911
Research Institution
CHICAGO, IL 60612-4305
United States

 Nonprofit College or University

RA is one of the most common chronic autoimmune disorders that can lead to complete joint
destruction and severe disability if untreated. There is no cure for RA and up to 50% of RA patients do not
respond to anti-TNF therapies as circulating Th-17/IL-17 levels are highly elevated subsequent to TNF
blockade. For this subset of RA patients, disruption of a novel pathway that impairs the synergy between TNF
(M1 macrophages) and IL-17 (Th-17 cells) cascades may resolve the critical barrier in RA treatment. Hence
objective of this project is to develop a therapeutic human TLR5 antibody (Ab) for RA patients whose disease
is driven by the cross-talk between the effector macrophages and T cells.We documented that ligation of TLR5 to its natural ligand expressed in the joints, transforms RA
peripheral blood (PB) cells into proinflammatory M1 macrophages which produce high levels of TNF, IL-1 and
IL-6. In addition, IL-6 produced from TLR5 driven M1 macrophages can differentiate the naïve T cells into
inflammatory RA TH-17 cells that secrete IL-17A, IL-17F, IL-22, IL-24, IL-26, CCL20 and GM-CSF. In mice,
systemic and local injection of a TLR5 agonist exacerbates joint swelling; conversely anti-TLR5 Ab treatment
alleviates collagen induced arthritis (CIA) joint inflammation.To investigate the role of TLR5 Ab as a potential treatment for RA, we have partnered with scientists at
Abwiz Inc. Using a TLR5 antigen, a human fragment antigen-binding (Fab) phage display library was screened
for TLR5 high affinity binders. Up to 40 positive clones were sequenced and 10 selected TLR5 Fab clones
were expressed, purified and assessed by ELISA for TLR5 binding and cross reactivity. Ten Fab clones were
examined by the Shahrara lab for TLR5 neutralization capacity in human and murine cells and one was
selected based on its superior blocking capacity.The overall goal of this project is to develop an anti-TLR5 Ab for RA therapy. In Phase I, our approach
is to enhance the affinity of anti-TLR5 Ab in order to reach a Kd value that is within the range of commercially
available Abs. Candidates provided through site directed mutagenesis using phage-display Ab library, will be
tested for their TLR5 blocking affinity in human cells. Subsequently, the most promising candidates will be
tested for their ability to abrogate RA synovial fluid from promoting inflammatory response in humanized RA
mouse model. The long term goal of this project is to generate a safe and completely novel TLR5 Ab for RA
patients that do not respond to the current therapies.A receptor has been identified in rheumatoid arthritis (RA) patients, which can strongly promote joint
inflammation and bone erosion. We show strong evidence that blocking the function of this receptor potently
alleviates the inflammatory response and bone loss in RA and preclinical models. The goal of this proposal is
to engineer a highly specific antibody against the identified receptor so that it can be used as a potential
therapy in RA patients.

* Information listed above is at the time of submission. *

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