Murine anti-mouse T cell monoclonal antibodies elicit anti-antibodies in mice: intra-species immunization model for estimating potential patient sensitization against humanized anti-T cell antibodies.

Humanization of immunosuppressive anti-T cell monoclonal antibodies (mAb) raises the question as to how completely it helps to avoid formation of neutralizing anti-antibodies (anti-Ab) in patients. To get more information on intra-species sensitization against anti-T cell mAb, we produced two immunosuppressive mouse IgG2a anti-mouse Thy-1.2 mAb (MmT1 and MmT5) in AKR/J mice and measured the potential of MmT1 to elicit inhibitory anti-Ab in AKR/J (H-2k), C57BL/6 (H-2b), congenic B10.BR (H-2k) and DBA/2 (H-2d) mice. After one injection once weekly for 4 weeks of 5 micrograms MmT1 (200 micrograms/kg) in C57BL/6 mice, without the use of any adjuvants, high concentrations of anti-Ab directed against MmT1 (300 micrograms/ml) and MmT5 (100 micrograms/ml) were measured by enzyme-linked immunosorbent assay. Similar concentrations of anti-Ab were found in immunized DBA/2 and less in B10.BR mice. No syngeneic anti-Ab could be produced in AKR/J. From the C57BL/6 mice, we raised anti-MmT1+, MmT5- idiotype (IDIO1) and anti-MmT1+, MmT5+ allotype (ALLO1) mAb. An in vivo test system was adapted to measure the inhibitory effects of circulating poly- or monoclonal anti-Ab. It revealed a reduction of in vivo depletion capacity not only of the sensitizing mAb (MmT1), but also of another anti-Thy-1.2 mAb (MmT5), with identical allotype but different idiotype. From this we conclude that intra-species immunization following injection of anti-T cell mAb can produce high titer inhibitory anti-idiotype and anti-allotype antibodies. Implications for hyperchimeric or fully human anti-T cell mAb are discussed.