GA101, a novel therapeutic type II CD20 antibody with outstanding efficacy and clear superiority in subcutaneous non-Hodgkin lymphoma xenograft models

3982

GA101 is the first humanized, glycoengineered CD20 antibody that can be classified as a type II CD20 antibody. It is currently in Ph I clinical trials. GA101 is characterized by: nM binding affinity for a CD20 type II epitope and hence reduced CDC activity; high cell death induction on B cells; and high ADCC potency due to an increased affinity for FcγRIIIa on effector cells. We studied the effects of GA101 on the growth of subcutaneous (s.c.) NHL xenograft models in SCID beige mice; a model primarily indicative of non-effector cell mediated mechanisms. In several aggressive NHL models GA101, both as single agent and combined with chemotherapy or targeted agents, demonstrated outstanding dose-dependent anti-tumor efficacy.
 Specifically, complete tumor remission and long-term survival was induced by GA101 in the s.c. SU-DHL4 diffuse large B cell lymphoma (DLBCL) xenograft model at a weekly dose of 30 mg/kg. By contrast, when rituximab, a classical type I antibody, was tested at similar or higher doses it was only able to reduce the rate of tumor progression.
 In clinical practice rituximab is applied in combination with chemotherapy resulting in synergistic activity of both therapeutic regimens and substantial clinical benefit compared to monotherapies. However, it has been argued that immune effector mediated efficacy might be impaired when combined with chemotherapy. We have shown that the type II CD20 antibody GA101 works in a synergistic and superior manner in combination with chemotherapy as well. Xenograft data in the s.c. WSU-DLCL2 (DLBCL) model demonstrate that GA101 works in concert with classical chemotherapeutic agents. More importantly, the combination of GA101 with chemotherapeutic agents is superior to the combination of these agents with rituximab.
 The apoptosis inhibitor Bcl-2 plays an essential role during the development of B cell malignancies. In order to investigate whether the mode of action of GA101 is compatible with inhibition of Bcl-2 a combination study in the SU-DHL4 model was designed. Bcl-2 inhibitors (dosed at MTD) or GA101 (at a suboptimal dose of 10 mg/kg) administered as single agents could only slow down tumor progression. Conversely, GA101 at the sub-optimal dose in combination with Bcl-2 inibitors exhibited outstanding synergistic activity resulting in the complete remission of all tumors.
 In summary, these data clearly demonstrate that GA101 represents a novel class of therapeutic CD20 antibodies with outstanding and unique efficacy compared to classical CD20 antibodies. Based on these preclinical data it is anticipated that the combination of the recognition of a type II epitope together with improved ADCC potency exclusive to GA101 will translate into superior clinically efficacy establishing GA101 as best in class anti-CD20 therapy.