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Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab.

Smolej L - Pharmgenomics Pers Med (2014)

Bottom Line: This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies.Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients.These results led to approval of obinuzutumab for the treatment of CLL.

View Article: PubMed Central - PubMed

Affiliation: 4th Department of Internal Medicine - Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.

ABSTRACT
Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of action of anti-CD20 monoclonal antibodies.Abbreviation: CLL, chronic lymphocytic leukemia.
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f1-pgpm-8-001: Mechanisms of action of anti-CD20 monoclonal antibodies.Abbreviation: CLL, chronic lymphocytic leukemia.

Mentions: Monoclonal antibodies in general have three possible mechanisms of action. These include: 1) antibody-dependent cellular cytotoxicity (ADCC), 2) complement-dependent cytotoxicity (CDC), and 3) direct growth inhibition and apoptosis, referred to as direct cell death (DCD) (Figure 1).29 Type II characteristics of obinutuzumab, namely stronger ADCC and direct cell death induction as well as weaker CDC were repeatedly demonstrated in comparison to known type I antibodies rituximab and ofatumumab. Enhanced ADCC was achieved by modifying the Fc fragment of obinutuzumab by glycoengineering (modification of glycosylation leading to afucosylated Fc fragment) and by amino acid substitution, which led to augmented binding to both high- and low-affinity FCγRIII on effector cells (eg, NK-cells and macrophages), resulting in ADCC up to 100-fold higher than rituximab.30,31 Interestingly, antibody-dependent cellular phagocytosis (ADCP) by macrophages was weaker with obinutuzumab than that with rituximab and ofatumumab.32 Obinutuzumab does not localize to membrane lipid microdomains on the target cells; in addition, it binds markedly less C1q than rituximab.33 The consequence is decreased CDC when compared to rituximab, especially ofatumumab.28 Immunofluorescence studies on Ramos cells showed that while rituximab was present at sites corresponding to lipid rafts, obinutuzumab formed stable complexes with CD20 at sites of cell-to-cell contact; this could be the explanation of stronger homotypic aggregation of target cells by obinutuzumab – another type II antibody feature.34 Different binding of type I vs type II antibodies also explain why B-cells can accommodate twice the number of type I antibodies compared with type II at saturating concentrations.28 Binding experiments showed that obinutuzumab recognizes a distinct but overlapping epitope of CD20 antigen compared to rituximab.28,34 Nevertheless, obinutuzumab binds in a different space orientation and with a wider elbow–hinge angle (by 30°) than rituximab.34 This is a consequence of amino acid sequence modification (substitution of valin for leucin at Kabat position 11) in immunoglobulin heavy chain elbow–hinge region – the site that affects the flexibility of the Fab′ and F(ab)′2 antibody domains. Reversal of this change resulted in partial loss of the type II antibody attributes, emphasizing the importance of spatial structure of the elbow–hinge region for the function of type II antibodies.28 Obinutuzumab is a potent direct cell death inductor as demonstrated by ability to kill CLL cells without the presence of a cross-linking antibody.32 Proposed mechanisms of DCD include caspase-independent apoptosis28 and nonapoptotic, actin-dependent, lysosome-mediated cell death involving reactive oxygen species.35,36 As a result of enhanced ADCC and DCD, obinutuzumab achieved superior B-cell depletion to rituximab in healthy volunteers and whole blood assays from CLL patients (Table 2).28


Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab.

Smolej L - Pharmgenomics Pers Med (2014)

Mechanisms of action of anti-CD20 monoclonal antibodies.Abbreviation: CLL, chronic lymphocytic leukemia.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325625&req=5

f1-pgpm-8-001: Mechanisms of action of anti-CD20 monoclonal antibodies.Abbreviation: CLL, chronic lymphocytic leukemia.
Mentions: Monoclonal antibodies in general have three possible mechanisms of action. These include: 1) antibody-dependent cellular cytotoxicity (ADCC), 2) complement-dependent cytotoxicity (CDC), and 3) direct growth inhibition and apoptosis, referred to as direct cell death (DCD) (Figure 1).29 Type II characteristics of obinutuzumab, namely stronger ADCC and direct cell death induction as well as weaker CDC were repeatedly demonstrated in comparison to known type I antibodies rituximab and ofatumumab. Enhanced ADCC was achieved by modifying the Fc fragment of obinutuzumab by glycoengineering (modification of glycosylation leading to afucosylated Fc fragment) and by amino acid substitution, which led to augmented binding to both high- and low-affinity FCγRIII on effector cells (eg, NK-cells and macrophages), resulting in ADCC up to 100-fold higher than rituximab.30,31 Interestingly, antibody-dependent cellular phagocytosis (ADCP) by macrophages was weaker with obinutuzumab than that with rituximab and ofatumumab.32 Obinutuzumab does not localize to membrane lipid microdomains on the target cells; in addition, it binds markedly less C1q than rituximab.33 The consequence is decreased CDC when compared to rituximab, especially ofatumumab.28 Immunofluorescence studies on Ramos cells showed that while rituximab was present at sites corresponding to lipid rafts, obinutuzumab formed stable complexes with CD20 at sites of cell-to-cell contact; this could be the explanation of stronger homotypic aggregation of target cells by obinutuzumab – another type II antibody feature.34 Different binding of type I vs type II antibodies also explain why B-cells can accommodate twice the number of type I antibodies compared with type II at saturating concentrations.28 Binding experiments showed that obinutuzumab recognizes a distinct but overlapping epitope of CD20 antigen compared to rituximab.28,34 Nevertheless, obinutuzumab binds in a different space orientation and with a wider elbow–hinge angle (by 30°) than rituximab.34 This is a consequence of amino acid sequence modification (substitution of valin for leucin at Kabat position 11) in immunoglobulin heavy chain elbow–hinge region – the site that affects the flexibility of the Fab′ and F(ab)′2 antibody domains. Reversal of this change resulted in partial loss of the type II antibody attributes, emphasizing the importance of spatial structure of the elbow–hinge region for the function of type II antibodies.28 Obinutuzumab is a potent direct cell death inductor as demonstrated by ability to kill CLL cells without the presence of a cross-linking antibody.32 Proposed mechanisms of DCD include caspase-independent apoptosis28 and nonapoptotic, actin-dependent, lysosome-mediated cell death involving reactive oxygen species.35,36 As a result of enhanced ADCC and DCD, obinutuzumab achieved superior B-cell depletion to rituximab in healthy volunteers and whole blood assays from CLL patients (Table 2).28

Bottom Line: This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies.Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients.These results led to approval of obinuzutumab for the treatment of CLL.

View Article: PubMed Central - PubMed

Affiliation: 4th Department of Internal Medicine - Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.

ABSTRACT
Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

No MeSH data available.


Related in: MedlinePlus