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Manocept, a derivative of FDA-approved 99mTc-Tilmanocept, exhibits diagnostic potential by specifically identifying macrophages in rheumatoid arthritis: a novel application of an existing drug
Nicholas Young1, Thomas J. Rosol1, Larry S. Schlesinger1, Frederick O. Cope2, Ramiro E. Toribio1, Wael Jarjour1
1The Ohio State University Wexner Medical Center, Columbus, Ohio, USA2Navidea Biopharmaceuticals, Inc., Dublin, Ohio, USA
June 11th
EULAR 2015
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Financial Interests Disclosure: I have no financial interests relative to this project to declare
Competing Interests Disclosure:Dr. Wael Jarjour- scientific advisory board member for
Macrophage Therapeutics (a division of Navidea Biopharmaceuticals, Inc.)
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Manocept Platform
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Glucose Backbone
Mannose
Therapeutics -Cytotoxins -Antagonist -Agonist
CD206Macrophage receptor
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Lymphoseek
99mTc-Tilmanocept (Lymphoseek) gamma emitting metastable isotope
half-life of 6.02 hours binds with high affinity and specificity to macrophage mannose receptor (MR, CD206)
Currently to facilitate preoperative and intraoperative lymphatic mapping identification of sentinel lymph nodes
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Wallace, A.M., et. al. Ann surg oncol 20:2590-2599, 2013.
Agrawal A., et. al. Ann surg oncol Online First- Feb, 2015.
Cope F, et al.. Nature; Supplement: Medical Imaging, 502(7473), 2013.Azad AK, et al. Journal of Cytology and Molecular Biology. 1:1, 2014.Azad AK, et al. J. Immunol. In revision.
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Hypothesis
CD206 is a suitable biomarker to target in rheumatoid arthritis for diagnostic and therapeutic development using Manocept
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rheumatoid arthritis (RA)
Rheumatoid arthritis (RA) is a chronic,
systemic disease causing autoimmune
inflammation and pathology throughout the body most noticeably in the joints
In the affected joints, RA is characterized by
macrophage infiltration and joint destruction. macrophages are key players in RA and are present in the synovium of a joint
affected by RA joint inflammation in RA patients can lead to crippling loss of function and severe
chronic pain
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https://www.rheumatology.org/Practice/Clinical/Patients
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RA - diagnosis
The most common tests for RA are negative 20% of the time with presentation of clinical symptoms
There are currently a few tools that are available to assess RA disease activity.
There is a clear need to develop agents for imaging RA
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http://www.uofmhealth.org/health-library/zm6061
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Objective
Determine if Manocept can be used as imaging agent in rheumatoid arthritis to provide
an effective diagnostic tool for prodromal RA to use as a monitor of disease activity or to
measure therapeutic responses
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Macrophages Lymphocytes
CD206
MDM—CD206 detection and specificity
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MDM--Manocept
CD
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Macrophages
Lymphocytes
Manocept
1 ml Manocept 10 ml Manocept
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Flow Cytometry of RA Synovial FluidManocept+
46.9 CD206+45.5
CD68+45.8
Manocept
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Manocept detection is specific to RA (flow cytometry)
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Manocept
Manocept+ / CD16+ Manocept+ / CD16+
OA RA
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Image Key: Red, Manocept-Cy3; blue (DAPI).
Manocept detection in synovial tissue from a RA patient with binding specificity
DAPI
Manocept 10x “cold” pre-incubation Merge
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Manocept-Cy3 co-localization with CD206 in RADAPI CD206 Manocept-cy3 Merge
RA
OA
Healthy
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Manocept detection is specific to RA (histology)
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Manocept-Cy3 in an in vivo model of RA Induction of RA in mice
Dba1 mice injected IP with Ab cocktail of 5 anti-cartilage antibodies
IP of E. coli LPS 3 days later Joints become swollen and have restricted motion by
day 6 Epifluorescent Imaging: ex vivo by IVIS performed
on days 7 and 9 2 hours after Manocept IV injection
Histology: Knee histopathology scored, H&E, F 4/80 16
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in vivo model of RA---H&E
Control mouse
RA mouse
Control mouse RA mouse
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in vivo model of RA---F 4/80
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Control mouse RA mouse
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Manocept-cy3 co-localization with CD206 in RA animal model
Control mouse
RA mouse
Control mouse
RA mouse
Control mouse
RA mouse
Elbow
Knee
Spleen
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Control mouse
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Manocept-Cy3 can image inflamed joints
RA mouse
Elbow Knee
Control mouse
RA mouse
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Results Manocept can be used to identify mannose receptor Flow cytometry:
macrophages in RA synovial fluid Levels of CD206 and Manocept are similar Manocept is detected with macrophage markers in RA synovial fluid
• Immunofluorescent microscopy:• Manocept+ / CD206+ co-localization is observed in RA synovial tissue,
but not in OA or healthy tissue• Manocept+ labeling is significantly greater in RA compared to OA or
healthy tissue• OA signals do not differ significantly from healthy tissue
• IVIS:• Manocept can be detected in inflamed joints in an
in vivo animal model of RA21
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Conclusion
Manocept-targeting of macrophages has the potential to detect immune-mediated inflammation in RA and could be used diagnostically or to monitor therapeutic efficacy
Future work: Build human cohort of prodromal and established
patients to test Lymphoseek Explore and further develop the cytotoxic, antagonistic,
and agonistic linkers to the Manocept platform
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Acknowledgements
Wael Jarjour, MDLai-Chu Wu, PhDHareth Madhoun, DOJeffrey HamptonMichael BrussAmanda KiblerHolly Steigelman
The Ohio State University Wexner Medical Center, Columbus, OHDepartment of Internal MedicineDivision of Rheumatology and Immunology
Department of Microbial Infection and ImmunityCenter for Microbial Interface Biology
Navidea Biopharmaceuticals, Dublin, OH
Frederick Cope, PhD MS FACN
The Ohio State University College of Veterinary Medicine
Larry S. Schlesinger, MDAbul K. Azad, PhDMurugesan V.S. Rajaram, PhD
Thomas Rosol, DVM, PhDRamiro E. Toribio, DVM, MS, PhDBrad Bolon, DVM, MS, PhD
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