Early phase development of anti-drug-antibodies in rheumatoid arthritis patients

The introduction of biopharmaceuticals (BP) has been a critical step forward in
care for RA and 10 BP are now licensed for the treatment of RA. In spite of
this progress, failure of response to BP is frequent and in most of the
registries, less than 50 % of patients are still on drug at 5 years. These
failures may be primary failures or secondary failures. The fact is that the
low level of responses becomes insufficient compared to the expectations. One
of the main potential causes of these failures of BP therapy response is the
development of ADAb in some patients. ADAb may decrease the efficacy of BPs by
neutralizing them or modifying their clearance and they may be associated with
BP-specific hypersensitivity reactions. The prediction, prevention and cure of
anti-drug (AD) immunization are thus major goals in BP development.
Humoral response against an antigen begins with a short-term massive antibody
production and continues with the development of long term memory
immunogenicity. Antibody-secreting plasmablasts can be detected in peripheral
blood only for a few days (5 to 10) after antigen encounter. They circulate in
transit to the bone marrow where they become long-living memory B cells. Thanks
to the process of affinity maturation, memory B cells are much more specific
and efficient in recognizing the antigen compared to plasmablasts. As a
consequence, at a second encounter with the antigen, the antibody response
driven by memory B cells is faster, stronger and more specific.
It has been shown that memory B cell generated against an antigen can be
clonally related to plasmablasts found in the peripheral blood few days after
the encounter with that antigen on the base of their B cell receptor (BCR)
sequence. By analyzing the mutations that occurred in the plasmablast BCR
sequence compared to the memory B cell BCR sequence, it is also possible to
follow the process of affinity maturation. The same has been proven to be true
the other way around: plasmablasts generated during a secondary humoral
response can be clonally related to memory B cell found before the second
encounter with the antigen.
In order to develop a (early) predictive tool for immunogenicity, it is
necessary to know which are the earliest markers of immunogenicity and how
immunogenicity then evolves. By sequencing the BCRs of anti-drug specific
plasmablast and memory B cell that form after the biological infusion, we can
identify some peculiar common traits that characterize biologicals
immunogenicity. Based on these common immunogenicity trait, we could
eventually be able to predict unresponsive patients before starting the
treatment or at least, after the first biological infusion.
This prospective study will assess the occurrence of early humoral responses
and ADAb formation using newly developed assay(s) in RA patients treated with
any of the BP treatments, to address the mechanism of early immunogenicity.
Patient-related factors that might predispose an individual to an immune
response will be taken into account: underlying disease, genetic background,
immune status, including immunomodulating therapy and dosing schedule.
Thus, novel approaches to characterize anti-drug lymphocytes responses will be
tested in patient materials (DNA, RNA, serum, PBMC). The objectives are to
understand the early cellular mechanisms causing AD responses that might
predispose an individual to an immune response.

PRIMARY OBJECTIVE
To identify the cellular mechanism behind early antidrug antibody (ADAb)
production related to humoral responses within first 3 months of BP treatment.

SECONDARY OBJECTIVES
- To identify the affinity maturation process in ADAb specific plasmablasts and
memory B cell
- To identify cellular biomarkers associated with the development of ADAb at
any time of treatment

Prospective cohort study in patients with rheumatoid arthritis (RA).
The total duration of study is 4 years, its include 36 months for inclusion
period and 12 months for duration of patient participation
STUDY DURATION FOR EACH PATIENT
Sampling period(s) will be the same for all BPs
1. M0/W0/D0 (Baseline)
2. W1 ± 1D
3. W2 ± 1D
4. M1/W4 ± 2D
5. M3/W12 ± 2W
6. M6/W26 ± 2W
7. M12/W52 ± 4W
- End-of-study : At W48-W56 after all the scheduled study procedures (e.g.
blood sampling) and after agreement by the investigator or sub-investigator
- Total study participation : 48 to 56 weeks
The study will be considered completed for a patient at the time he/she
completes all the scheduled study procedures.

Since the BP therapy will be prescribed by the Treating Physician this study is
not an intervention trail. Therefore, the pre-screening of patients for
administration of BP therapy and safety follow-up will be done according to
national guidelines for BP*s. This will be the responsibility of the Treating
Physician.

The procedures of this study are;
1. gathering clinical data
2. drawing of blood for further analysis
Blood drawing has a relatively low risk of adverse reactions. Due to the fact
that this study is accompanied with a small risk of adverse reactions we do not
expect serious adverse reactions to occur.