New Treatment Modalities: Update on GA101

1. 2008 New Treatment Modalities:Update on GA101

2. GA101, a novel therapeutic type II CD20 antibody with outstanding anti-tumour efficacy in non-Hodgkin lymphoma xenograft models and superior B-cell depletion Umana P, et al. ICML 2008; Abstract 98.

3. Background • Umana and colleagues presented data at ASH 2006 on GA101, the first humanized, new-generation, glycoengineered, type II, anti-CD20 antibody.1 • At ICML 2008, Umana and colleagues presented updated results fromin vitro and in vivo studies of GA101.2 • GA101 mechanism of action differs from type I MABs, such as rituximab, ocrelizumab, and ofatumumab, in the following ways:3 • increased direct cell death due to type II epitope recognition and elbow-hinge modification • increased ADCC via increased affinity to the ADCC receptor FcyRIIIa • lower CDC activity as compared with rituximab 1. Umana P, et al. ASH 2006; Abstract 229. 2. Umana P, et al. ICML 2008; Abstract 98. 3. Maloney DG. Hematology Am Soc Hematol Educ Program 2007;2007:226–232. ADCC = antibody-dependent cell-mediated cytotoxicity ASH = American Society of Hematology CDC = complement-dependent cytotoxicityMAB = monoclonal antibody

4. Umana P, et al. ICML 2008; Abstract 98.

5. Key findings • GA101 brought about increased direct cell death in both a panel of NHL cell lines and inex vivo samples from patients with a variety of B-cell malignancies • In B-cell depletion assays with whole blood from healthy donors and from B-cell leukemic patients, an assay combining ADCC-, CDC- and apoptosis-mediated mechanisms of action, GA101 was significantly more potent and efficacious than other CD20 antibodies • Higher antibody concentration of GA101 was needed to deplete B-cells in B-cell patient blood • In the SU-DHL-4 xenograft model, treatment with a 30 mg/kg weekly dose of GA101 resulted in superior efficacy in terms of tumour growth inhibition and complete tumour remission as compared with rituximab • Tumours that progressed under first-line rituximab treatment responded to second-line treatment with GA101 • Treatment with GA101 increased the median and overall survival in the orthotopic-disseminated Z138 MCL model as compared with rituximab • In the hCD20 transgenic mice, GA101 demonstrated superior B-cell depletion. The increased B-cell depletion extended into the peripheral lymphoid compartments and to the range of B-cell subsets targeted • Analogous findings were observed in Cynomolgus monkeys, where the efficacy of GA101 in depleting B-cells in lymphoid tissues was compared with that of rituximab ADCC = antibody-dependent cell-mediated cytotoxicityCDC = complement-dependent cytotoxicityNHL = non-Hodgkin’s lymphoma Umana P, et al. ICML 2008; Abstract 98.

6. Umana P, et al. ICML 2008; Abstract 98.

7. Umana P, et al. ICML 2008; Abstract 98.

8. Umana P, et al. ICML 2008; Abstract 98.

9. Key conclusions • GA101 is a fully humanized monoclonal antibody that recognizes a CD20 type II epitope • GA101 exhibits superior ADCC, direct cell-death induction, and reduced CDC • Treatment with GA101 results in superior B-cell depletion in whole blood assay • GA101 treatment demonstrates superior efficacy in various NHL xenograft models, including diffuse large B-cell, mantle cell, and follicular lymphomas • In vivo efficacy studies in Cynomolgus monkeys and huCD20 transgenic mice confirm the in vitro findings • GA101 is currently being assessed in phase I/II trials (NCT00517530) ADCC = antibody-dependent cell-mediated cytotoxicityCDC = complement-dependent cytotoxicityNHL = non-Hodgkin’s lymphoma Umana P, et al. ICML 2008; Abstract 98.