Response to: monoclonal antibodies targeting CD20.

Dear Editor,

Please allow us to briefly reply to the comments by Dr. Goldenberg and colleagues. As stated in the disclosures, some authors are employees of Roche Glycart AG or Roche Diagnostics GmbH and have contributed to the (non-) clinical development of the glycoengineered Type II CD20 antibody GA101 (obinutuzumab). In writing this review, we aimed to give a general overview of the epitopes, structural and mechanistic features of CD20 antibodies in development. Due to length restrictions, this work could not necessarily be comprehensive and did not cover, for example, bispecific antibodies. Furthermore, the discussion of clinical data was intentionally not within the scope of this review because it is covered in other expert reviews.-

Overall, we do not agree with the conclusions drawn by Dr. Goldenberg and colleagues. In their publication, Goldenberg et al. show indeed that veltuzumab has a slower off-rate than rituximab on B cells, however, scatchard analysis showed that the KD values were comparable, with 8.6 nM for rituximab and 10.8 nM for veltuzumab. More importantly, this finding did not appear to translate into major functional differentiation. Veltuzumab showed in vitro anti-proliferative activity, antibody-dependent cell-mediated cytotoxicity and B cell depletion in human peripheral blood lymphocytes of healthy volunteers comparable to rituximab. There was only a significant difference in complement-dependent cytotoxicity (CDC) induction reported where veltuzumab was less than 2-fold more potent than rituximab. While statistically significant, we think that this small difference in EC50 values is not biologically relevant, in particular, as the authors demonstrate themselves by depletion of natural killer cells and neutrophils that the in vivo efficacy of veltuzumab in xenograft models relies on antibody-dependent effector cell function, but not on CDC. In light of these in vitro data the reported superiority of veltuzumab over rituximab in nonclinical xenograft models as well as a potential for clinical superiority is difficult to rationalize.

We believe that it is not justified to claim clinical superiority of the 80 mg (for the subcutaneous formulation) or 80 mg/m2 (for intravenous infusions) weekly x 4 doses of veltuzumab over the standard rituximab regimen of 375 mg/mm2 based solely on a historical comparison of complete response (CR)/unconfirmed CR rates from non-randomized Phase 1/2 clinical trials in (relapsed/refractory) follicular non-Hodgkin lymphoma (NHL) patients as it is stated in the letter of Goldenberg and colleagues. In line with this, the cited publications by Morschhauser et al. and Negrea et al. do not claim superiority over rituximab. To claim superiority, the authors would have to provide clinical data where veltuzumab and rituximab are compared head-to-head at the respective (standard) doses.

The dose and schedule of obinutuzumab (GA101) cannot be extrapolated from the rituximab dose and schedule due to the differences in the antibodies and their mechanisms of action. In the case of obinutuzumab, we have shown that by increasing the dose from 10 to 30 mg/kg in the SU-DHL4 diffuse large B cell lymphoma (DLBCL) nonclinical xenograft model we could induce complete tumor remissions, whereas increasing the dose of rituximab from 10 to 30 mg/kg did not result in enhanced efficacy and only slowed down tumor progression. These nonclinical data and data from Phase 2 clinical trials comparing doses of 400/400 mg vs 1600/ 800 mg obinutuzumab in relapsed/refractory iNHL and DLBCL patients, support the rationale that in the case of obinutuzumab a flat dose of 1000 mg is studied in clinical trials. This may be particularly true for patients with higher tumor loads. We also want to point out that there is no clinical evidence available supporting the statement that higher doses of CD20 antibodies result in more pronounced side effects.

In the best interest of patients, we believe that novel CD20 antibodies such as obinutuzumab, ofatumumab or veltuzumab have to be studied in clinical trials first, at the optimal dose for that antibody as determined in clinical Phase 1/2 studies, and second, in randomized clinical trials in direct comparison to the approved/standard of care rituximab based regimen. This belief is the basis of the development paradigm for obinutuzumab, which is currently being studied in combination with chemotherapy head-to-head to rituximab in three first line Phase 3 clinical trials in CLL, indolent NHL and DLBCL. Ultimately, only these clinical data can tell whether nonclinical findings translate into superior clinical benefit in patients with B cell malignancies.