Update on obinutuzumab in the treatment of B-cell malignancies

Abstract

Clinical data are now emerging confirming the promise of the initial preclinical data that demonstrated superior efficacy of obinutuzumab over rituximab at similar dosing. The emerging randomized Phase III data from older comorbid patients with previously untreated CLL demonstrated significant improvements in molecular remission rates and median progression-free survival of obinutuzumab plus chlorambucil versus rituximab plus chlorambucil. This emerging data provide reasons to be optimistic that outcomes for patients with B-cell malignancies can be further improved with obinutuzumab.

A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19+tumor cells

“…[3][4][5] Nevertheless, the demand for even more efficacious treatments catalyzed the development of a new class of bispecific immune cell-recruiting antibodies. Such antibodies specifically, with extreme potency, recruit particular immune effector cells, and are able to recruit NK cells, 30 T cells, 23 …”

“…The principal optimizations pursued are enhancement of effector function and selection of tumor-targeting cellular marker. The Fc-optimization strategy relies upon engineering the Fc-domain to achieve more potent interaction with the Fcg receptors expressed on endogenous immune effector cells; Fc-optimized antibodies, targeting CD20, obinutuzumab, 3 and targeting CCR4, mogamulizumab, 4 have been approved, and another targeting CD19, MOR208, 5 has entered clinical trials.…”

Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeling

“…In addition to the complex type N-glycan, the specificity of Endo-S2 was further tested with high-mannose type (HM) Man 9 GlcNAc oxazoline (7) and sialo hybrid type (Hyb) Neu5AcGalGlcNAcMan 5 GlcNAc oxazoline (5) as donor substrate in the transglycosylation reactions. The reactions led to the formation of the corresponding homogeneous glycoforms, (8) and (6), respectively (Fig.…”

“…Compelling experimental data have shown that glycosylation can have profound impacts on the stability, biological functions, and overall therapeutic efficacy of antibodies (4 -7). For example, core-fucosylation of Fc glycans could significantly reduce the antibodydependent cellular cytotoxicity, and antibodies with low content of core-fucosylation have shown improved therapeutic efficacy in anti-cancer therapy (8,9). On the other hand, it has been reported that the terminal ␣2,6-sialylated Fc glycoform, a minor component in the intravenous immunoglobulin, is responsible for the anti-inflammatory activity of intravenous immunoglobulin as demonstrated in animal models (10 -13).…”

“…However, natural and recombinant antibodies are usually produced as heterogeneous glycoforms that are difficult to separate for further probing the structure-activity relationships of antibodies. Moreover, for a majority of anti-cancer mAbs on the market that rely on antibody-dependent cellular cytotoxicity as a major mechanism of the therapeutic efficacy, the most active non-fucosylated glycoforms are usually present as minor fractions among the heterogeneous mixtures (8,9). Thus, methods that can lead to the production of structurally well defined, homogeneous glycoforms of antibodies are highly desirable for both functional studies and for the development of better antibody-based therapeutics.…”