Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia

Cheney, Carolyn; Stephens, Deborah M.; Mo, Xiaokui; Rafiq, Sarwish; Butchar, Jonathan P.; Flynn, Joseph M.; Jones, Jeffrey A.; Maddocks, Kami J.; O'Reilly, Adrienne; Ramachandran, Abhijit; Tridandapani, Susheela; Muthusamy, Natarajan; Byrd, John C.

doi:10.4161/mabs.28282

Cited by 39 publications

(21 citation statements)

References 19 publications

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“…ADCC assays have been previously used as a surrogate measure of the cellular cytotoxicity of CD20 mAbs (20,23,43). Our data showed that NK cell ADCC did not predict ADCP capacity, a conclusion compatible with published data stating that the distance of mAb binding epitopes from the cell membrane differentially affects the ability to activate ADCC (more proximal) or ADCP (more distal; ref.…”

Section: Discussionsupporting

confidence: 88%

Cellular Cytotoxicity of Next-Generation CD20 Monoclonal Antibodies

VanDerMeid

Elliott

Baran

et al. 2018

Cancer Immunology Research

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CD20 monoclonal antibodies (CD20 mAb) induce cellular cytotoxicity, which is traditionally measured by antibody-dependent cellular cytotoxicity (ADCC) assays. However, data suggest that antibody-dependent cellular phagocytosis (ADCP) is the primary cytotoxic mechanism. We directly compared ADCP versus ADCC using primary human cells. After establishing the primacy of ADCP, we examined next-generation CD20 mAbs, including clinically relevant drug combinations for their effects on ADCP. ADCP and ADCC induction by rituximab, ofatumumab, obinutuzumab, or ocaratuzumab was measured using treatment-naïve chronic lymphocytic leukemia (CLL) target cells and either human monocyte-derived macrophages (for ADCP) or natural killer (NK) cells (for ADCC). Specific effects on ADCP were evaluated for clinically relevant drug combinations using BTK inhibitors (ibrutinib and acalabrutinib), PI3Kδ inhibitors (idelalisib, ACP-319, and umbralisib), and the BCL2 inhibitor venetoclax. ADCP (∼0.5-3 targets/macrophage) was>10-fold more cytotoxic than ADCC (∼0.04-0.1 targets/NK cell). ADCC did not correlate with ADCP. Next-generation mAbs ocaratuzumab and ofatumumab induced ADCP at 10-fold lower concentrations than rituximab. Ofatumumab, selected for enhanced complement activation, significantly increased ADCP in the presence of complement. CD20 mAb-induced ADCP was not inhibited by venetoclax and was less inhibited by acalabrutinib versus ibrutinib and umbralisib versus idelalisib. Overall, ADCP was a better measure of clinically relevant mAb-induced cellular cytotoxicity, and next-generation mAbs could activate ADCP at significantly lower concentrations, suggesting the need to test a wide range of dose sizes and intervals to establish optimal therapeutic regimens. Complement activation by mAbs can contribute to ADCP, and venetoclax, acalabrutinib, and umbralisib are preferred candidates for multidrug therapeutic regimens. .

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Section: Discussionsupporting

confidence: 88%

Cellular Cytotoxicity of Next-Generation CD20 Monoclonal Antibodies

VanDerMeid

Elliott

Baran

et al. 2018

Cancer Immunology Research

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“…For example, compared with rituximab, ofatumumab exhibits increased CDC by binding to a different CD20 epitope [24]. Fc alterations are illustrated by ocaratuzumab (AME-133v), which exhibits increased ADCC via an amino acid substitution in the Fc domain that alters Fcc receptor (FccR) interaction [27].…”

Section: Introductionmentioning

confidence: 99%

Obinutuzumab in hematologic malignancies: Lessons learned to date

Illidge

Klein

Sehn

et al. 2015

Cancer Treatment Reviews

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The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

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“…It was optimized through protein engineering for increased CD20 affinity and greater ability to mediate ADCC [77]. In preclinical studies, ocaratuzumab is~20 times more effective at mediating ADCC at very low concentrations that may facilitate sub-cutaneous dosing [78]. This antibody induces higher NK cell-mediated ADCC over rituximab and ofatumumab and in a similar way to obinutuzumab.…”

Section: Scientific Rationalementioning

confidence: 97%