IMMUNOMODULATING IL-6 ACTIVITY BY MURINE MONOCLONAL-ANTIBODIES

The human anti-mouse immunoglobulin antibody (HAMA) response, which oc curs frequently after injection of murine monoclonal antibodies (MAb) directed against cellular targets, has been reported extensively in se veral studies. We analysed here HAMA in 12 patients (six with multiple myeloma, MM, and six with metastatic renal cell carcinoma, MRCC) who were treated with B-E8, an IgG1 MAb against interleukin-6 (IL-6). Effi ciency of the treatment was evidenced by the drop in the serum levels of C reactive protein (CRP), of which the in vivo production is under the control of IL-6. Three patients with MM and the six patients with MRCC became immunized to the injected MAb. HAMA appeared between days 7 and 15 after the beginning of the treatment. The nine patients made IgG antibodies; four also made IgM. All of immunized patients made ant i-idiotype antibodies specific to B-E8. Two of them also developed HAM A directed to murine IgG1 isotype; in these two patients B-E8 MAb clea red rapidly from the circulation with loss of treatment efficiency. In the patients who developed only antiidiotype antibodies, serum levels of B-E8 remained unchanged and CRP production remained inhibited, ind icating that treatment efficiency was not affected by the presence of HAMA. Circulating B-E8 MAb were still able to bind to IL-6 and to inhi bit IL-6-independent proliferation despite the presence of anti-idioty pic HAMA. Therefore, in contrast to HAMA against MAb directed against cellular targets, HAMA against anti-IL-6 MAb idiotopes led neither to clearance nor to functional inactivation of the injected MAb. This was further shown by resuming the B-E8 treatment with success in a patien t who still had anti-idiotypic HAMA.