T10B9 monoclonal antibody: a short-acting nonstimulating monoclonal antibody that spares gammadelta T-cells and treats and prevents cellular rejection

Abstract

T10B9.1A-31/MEDI-500 is a nonmitogenic immunoglobulin M kappa murine monoclonal antibody (mAb) directed against the alpha-beta (alphabeta) heterodimer of the T-lymphocyte receptor complex. The hybridoma was first produced by fusing spleen cells from BALB/C mice immunized with human peripheral blood T-lymphocytes with SP2/O-Ag14 mutant myeloma cells. The mAb is produced and purified using multistep ion exchange and molecular sieve chromatography protocols. T10B9 has been used successfully to treat acute cellular rejection in renal transplantation and as an immunosuppression induction agent in heart and simultaneous kidney-pancreas transplantation. Because T10B9 is nonmitogenic and causes minimal cytokine release, both treatment of rejection and induction of immunosuppression were accomplished with significantly fewer and milder untoward effects (cytokine release syndrome) than its comparator OKT3. Since T10B9 is directed against the alphabeta heterodimer of the CD3 epitope, it spares the gamma delta (gammadelta) region. These gamma delta (gammadelta) T cells have a unique role in the immune response controlling many serious human diseases and perhaps facilitating the development of immunologic tolerance. T10B9 has a relatively short duration of action, depleting T cells for only 10 to 14 days, unlike the protracted depletion seen with thymoglobulin and Campath-1H. There is no B-lymphocyte depletion with T10B9 as there is with both of the aforementioned reagents. The lack of prolonged lymphocyte depletion may account for less infection observed with T10B9 treatment.

Keywords: Campath-1H; OKT3; T10B9.1A-31; monoclonal antibody; thymoglobulin; γδ T-cell.

Figure 1

T and B cell response and peak incidence of opportunistic infections after thymoglobulin, T10B9 and Campath^® administration.

Figure 2

Flow cytometric analysis of lymphoid cells in peripheral blood after administration of T10B9.1A-31, OKT3 or TCR-1 (anti-T cell receptor αβ monoclonal antibody [mAB]). There is early T-lymphocyte depletion with re-expression of the CD4 and CD8 epitopes. There is persistent modulation of the CD3/TCR αβ region in these phenotypically altered T cells for 10 days while the mABs are being administered with repopulation over 15–40 days.

Figure 3

Cytokine release in vivo in patients undergoing treatment for acute cellular rejection with T10B9 or OKT3.

Figure 4

T10B9 reverses rejection without the cytokine-induced rise in the serum creatinine seen with OKT3.

Figure 5

Flow cytometric analysis of peripheral blood T lymphocytes after control (no modulation), OKT3 or T10B9. T10B9 modulation shows a persistent population of γδ T cells and an absence of αβ T cells whereas both are absent after OKT3 modulation consistent with modulation of the CD3 epitope.