Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
XmAb®5871 is a humanized and Fc-engineered antibody that coengages CD19, part of the B cell receptor (BCR) complex, with the inhibitory receptor FcγRIIb (CD32b). This antibody is in clinical development as a potential therapy for RA and SLE, and we have previously characterized its immunosuppressive effects on B cells from normal and SLE donors. In this study, we assessed whether XmAb5871 similarly inhibits activation of RA B cells. Because XmAb5871 activity requires its Fc domain to bind with high affinity to FcγRIIb, we also assessed whether rheumatoid factor (RF), an anti-IgG Fc autoantibody, could interfere with its therapeutic mechanism.
Methods:
Blood from RA (N = 50) and normal (N = 72) donors was obtained with IRB approval. PBMC were analyzed by flow cytometry for expression of CD19, CD27, CD32b and CD86. Phosphorylation of FcγRIIb following incubation of PBMC with XmAb5871 was determined by phosphowestern blotting. XmAb5871-mediated suppression of intracellular calcium flux triggered by anti-CD79b in PBMC loaded with Fluo-4 NW dye was quantified by flow cytometry. Inhibition by XmAb5871 of CD86 expression on anti-CD79b-stimulated B cells was determined in whole blood. Plasma RF and ACPA levels were measured by ELISA. Demographic and clinical characteristics of RA patients were correlated with results from in vitro assays.
Results:
RA and normal B cells expressed CD19 and CD32b, the targets of XmAb5871. There was a smaller memory (CD27+) B cell compartment in RA (P = 0.003). CD32b expression was higher on naive (CD27-) (P = 0.0018) but not on memory B cells (P = 0.85) from RA vs. normal donors. BCR-mediated calcium flux was suppressed by XmAb5871 in RA and in normal B cells (67% vs. 50%, respectively; P = 0.0038). This inhibition was associated with FcγRIIb activation in RA and normal B cells (average 10-fold induction in both). Baseline CD86 expression was increased in naive and particularly in memory B cells of RA donors (P = 0.04 and < 0.0001, respectively). XmAb5871 efficiently inhibited CD86 induction in RA and normal B cells (76% vs. 62%, respectively; P = 0.0055). Notably, there was no effect of RF or ACPA levels on drug efficacy (R2= 0.002 and 0.021, respectively). Among RA patients, functional effects of XmAb5871 did not correlate with age, sex, years from diagnosis, extra-articular manifestations, tender or swollen joint counts, DAS28, erosive disease, or use of methotrexate, hydroxychloroquine, corticosteroids, or TNF antagonists. A history of rituximab treatment was associated with fewer memory B cells and reduced CD32b expression (P = 0.003 and 0.040, respectively). Nonetheless, the functional effects of XmAb5871 on B cells from these patients were not different from those in the RA cohort at-large.
Conclusion:
The FcγRIIb inhibitory pathway in B cells from RA patients can be amplified by an antibody engineered to co-engage FcγRIIb and CD19 with high affinity. The potency observed across multiple measures of B cell function in RA and normal donors and the lack of interference by physiological levels of RF and ACPA in RA patient sera suggests that XmAb5871 may represent a new therapeutic strategy to suppress autoreactive B cell populations in RA and related autoimmune diseases.
Disclosure:
S. Y. Chu,
Xencor,
1,
Xencor,
3;
K. Yeter,
None;
R. Kotha,
None;
E. Pong,
Xencor,
1,
Xencor,
3;
Y. Miranda,
Xencor,
1,
Xencor,
3;
H. Chen,
Xencor,
1,
Xencor,
3;
S. H. Lee,
Xencor,
1,
Xencor,
3;
I. Leung,
Xencor,
1,
Xencor,
3;
J. R. Desjarlais,
Xencor,
1,
Xencor,
3;
W. Stohl,
Xencor,
2;
D. E. Szymkowski,
Xencor,
1,
Xencor,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-rheumatoid-arthritis-b-cells-by-xmab5871-an-anti-cd19-monoclonal-antibody-that-co-engages-the-b-cell-antigen-receptor-and-the-fc%ce%b3riib-inhibitory-receptor/