HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs

Abstract

The anti-HLA-E IgG2a mAbs, TFL-006 and TFL-007, reacted with all HLA-I antigens, similar to the therapeutic preparations of IVIg. Indeed, IVIg lost its HLA reactivity, when its HLA-E reactivity was adsorbed out. US-FDA approved IVIg to reduce antibodies in autoimmune diseases. But the mechanism underlying IVIg-mediated antibody reduction could not be ascertained due to the presence of other polyclonal antibodies. In spite of it, the cost prohibitive high or low IVIg is administered to patients waiting for donor organ and for allograft recipients for lowering antiallograft antibodies. A mAb that could mimic IVIg in lowering Abs, with defined mechanism of action, would be highly beneficial for patients. Demonstrably, the anti-HLA-E mAbs mimicked several functions of IVIg relevant to suppressing the antiallograft Abs. The mAbs suppressed activated T cells and anti-HLA antibody production by activated B cells, which were dose-wise superior to IVIg. The anti-HLA-E mAb expanded CD4+, CD25+, and Foxp3+ Tregs, which are known to suppress T and B cells involved in antibody production. These defined functions of the anti-HLA-E IgG2a mAbs at a level superior to IVIg encourage developing their humanized version to lower antibodies in allograft recipients, to promote graft survival, and to control autoimmune diseases.

Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance

“…Of the 235 hybidomas generated, mAbs secreted by 214 hybridomas were reactive to HLA-E. These mAbs included both monospecific [35,98] and polyreactive (with other HLA-Ia and HLA-Ib molecules) [98,101]. Table 5…”

Therapeutic Potential of HLA-I Polyreactive mAbs Mimicking the HLA-I Polyreactivity and Immunoregulatory Functions of IVIg

“…To further ascertain that the mAbs recognized only the OCs, we compared the binding of mAb TFL-006 on LABScreen SABs (One Lambda, Inc., Canoga Park, CA, USA), which contained an admixture of OCs and CCs and with LIFECODES SABs (LSA Class I 03203F beads; Immucor, Norcross, GA, USA) that was devoid of HLA-I OCs [ 45 , 46 , 47 , 48 ]. The results presented in Table 5 show that the mAb TFL-006 did not bind to any of the alleles of the isoforms of HLA-I on LIFECODES SABs, confirming that mAb TFL-006 recognized only the OCs and did not bind to CCs on the LIFECODES beads.…”

“…Note that IVIg preparations used in this study failed to upregulate Tregs, in contrast to TFL-007a, which significantly upregulated Treg cells at dilution 1/10. This figure is original but derived and modified from a previous report [ 48 ].…”

Kinetics of interaction between polyreactive immunoglobulins and antigen

“…Earlier we named these molecules as polyreactive immunoglobulins (PRIGs) [2], which points on their nature, and also on their completely unspecific binding with antigens. Nevertheless, most researchers until present name them as polyreactive antibodies [3][4][5][6][7][8][9][10]. Meantime, the interest to those important molecules increases greatly.…”

“…Recent studies of PRIGs properties point to the variety of their functions and participation in quite different biological processes [3][4][5][6][7][8][9][10][11][12]. It alludes to their important role in the organism, although their basic functions and role in development of different pathologies until now remain insufficiently studied and understood.…”