Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Current therapies have shown tremendous progress in the treatment of rheumatoïd arthritis (RA). However, a substantial group of RA patients are still refractory to these therapies or develop resistance. RA patients that are resistant to anti-CD20 therapy illustrate the need for therapies targeted against cells of the late B cell lineage. We identified CD319, a marker of differentiated B cells as a potential target for therapy of RA.
Methods: A humanized antibody PDL241 directed against CD319 was generated. The binding of PDL241 to human tissues was analyzed by immunohistochemistry and FACS analysis of PBMC. Functional activity of PDL241 on PBMC was demonstrated in vitro and in a HuSCID mouse model. PDL241 is a primate specific antibody and safety and efficacy was tested in a collagen-induced arthritis (CIA) model in the rhesus monkey. The rhesus CIA model is an autoimmune-mediated model of polyarthritis with inflammation and erosion of joints that shares several important cellular and histopathological features with RA.
Results: We found that CD319 was expressed on plasma cells, but not CD20 positive B cells, in rheumatoid arthritis synovial tissues. In cultures of PBMC, PDL241 bound plasmablasts and plasma cells but not naïve and memory B cells, and inhibited the production of immunoglobulins in an Fc-dependent manner in vitro by reducing the numbers of late stage B cell lineage cells. High levels of CD319 on plasmablasts and plasma cells rendered them susceptible to ADCC mediated by NK cells. PDL241 also was able to reduce production of human IgM in a PBMC-transfer HuSCID model. Finally, PDL241 showed a beneficial activity in a rhesus macaque model of collagen-induced arthritis (CIA). Treatment with PDL241 resulted in a reduction of collagen-specific IgG and IgM production in the early phase of the disease leading to a reduction in joint swelling and the subsequent destruction of cartilage and bone.
Conclusion: CD319 was identified as a potential therapeutic target in RA following analysis of expression and in functional assays of IgM production from PBMC. The functional activity of PDL241 in the rhesus CIA model further supported the promise of targeting CD319 in RA. Development of PDL241 was halted due to immunogenicity observed in non-human primate models; however, the current study demonstrated the strong potential of CD319 as a therapeutic target in a range of autoimmune diseases, including RA, where CD319-expressing cells have a role in the pathology.
Disclosure:
M. P. M. Vierboom,
None;
J. Woo,
None;
H. Kwon,
Abbott Biotherapeutics,
3;
D. Chao,
Abbott Biotherapeutics,
3;
S. Ye,
Abbott Biotherapeutics,
3;
J. Li,
Abbott Biotherapeutics,
3;
K. Lin,
Abbott Biotherapeutics,
3;
I. Tang,
Abbott Biotherapeutics,
3;
N. Belmar,
Abbott Biotherapeutics,
3;
T. Hartman,
Abbott Biotherapeutics,
3;
E. Breedveld,
None;
B. A. ‘t Hart,
None;
G. C. Starling,
Abbott Biotherapeutics,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pdl241-a-novel-humanized-monoclonal-antibody-reveals-cd319-as-a-therapeutic-target-for-rheumatoid-arthritis/