Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective

Desjarlais, John R.; Lazar, Greg A.; Zhukovsky, Eugene A.; Chu, Seung Y.

doi:10.1016/j.drudis.2007.08.009

Cited by 127 publications

(114 citation statements)

References 89 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…1,2). Although it is difficult to assess the contribution of each of these mechanisms in their in vivo efficacy, clinical trial results support an important role of antibody-dependent cell-mediated cytotoxicity (ADCC) for both lymphomas and solid tumors (3). The affinity between the Fc portion of human IgG1 and FcgRIIIa (CD16a), an activating receptor mostly expressed by natural killer (NK) cells, monocytes, and macrophages, has a profound impact on ADCC exerted by antibodies (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…Several approaches such as site-directed mutagenesis, computational structure-based design, glycosylation engineering, and selection-based methods have been used to increase Fc binding to activating receptors (FcgRI, FcgRIIa, and FcgRIIIa) and to decrease their interaction with inhibitory FcgRIIb (3,13,14). Variants possessing up to 100-fold increased affinity for FcgRIIIa, resulting in 100-fold enhanced in vitro ADCC (3,15), have been selected.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Rozan

Cornillon

Pétiard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Antibody-dependent cell-mediated cytotoxicity, one of the most prominent modes of action of antitumor antibodies, suffers from important limitations due to the need for optimal interactions with Fcg receptors. In this work, we report the design of a new bispecific antibody format, compact and linker-free, based on the use of llama single-domain antibodies that are capable of circumventing most of these limitations. This bispecific antibody format was created by fusing single-domain antibodies directed against the carcinoembryonic antigen and the activating FcgRIIIa receptor to human Ck and CH1 immunoglobulin G1 domains, acting as a natural dimerization motif. In vitro and in vivo characterization of these Fab-like bispecific molecules revealed favorable features for further development as a therapeutic molecule. They are easy to produce in Escherichia coli, very stable, and elicit potent lysis of tumor cells by human natural killer cells at picomolar concentrations. Unlike conventional antibodies, they do not engage inhibitory FcgRIIb receptor, do not compete with serum immunoglobulins G for receptor binding, and their cytotoxic activity is independent of Fc glycosylation and FcgRIIIa polymorphism. As opposed to anti-CD3 bispecific antitumor antibodies, they do not engage regulatory T cells as these latter cells do not express FcgRIII. Studies in nonobese diabetic/severe combined immunodeficient gamma mice xenografted with carcinoembryonic antigen-positive tumor cells showed that Fab-like bispecific molecules in the presence of human peripheral blood mononuclear cells significantly slow down tumor growth. This new compact, linker-free bispecific antibody format offers a promising approach for optimizing antibody-based therapies.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Rozan

Cornillon

Pétiard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Interaction of human IgG antibodies with Fcγ receptors and the complement pathway (C1q) is of critical importance for antibody function as the PD and safety profiles of therapeutic antibodies in vivo can be partly regulated by these interactions (4,5,9,11,32). Engagement of antibody with various immune cells and complement proteins can result in activation of effector functions like antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), respectively (94,95). Optimization of antibody interactions with immune effector cells or complement proteins has been employed to impact favorably the clinical efficacy profile of therapeutic antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…Optimization of antibody interactions with immune effector cells or complement proteins has been employed to impact favorably the clinical efficacy profile of therapeutic antibodies. Engineering of antibodies with enhanced affinity for Fcγ receptors has resulted in greater effector activation and killing of antibody-coated target cells (94). Additionally, modification of the n-glycans attached to the antibody constant region has been employed for enhancing antibody ADCC-mediated activity (95)(96)(97).…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

View full text Add to dashboard Cite

Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

show abstract

“…Human Fcg receptors are expressed by a range of immune cell populations, including B cells, dendritic cells, macrophages, mast cells, NK cells and neutrophils (Desjarlais et al, 2007 Nimmerjahn and Ravetch, 2008). The consequence of immune cell engagement by antibodies is tightly controlled by the balance of activatory and inhibitory Fc-receptor binding.…”

Section: Fc-mediated Mechanisms Of Immune System Engagementmentioning

confidence: 99%

The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

Griggs¹,

Zinkewich-Péotti²

2009

Br J Cancer

View full text Add to dashboard Cite

A number of antibody products have now become accepted as effective anti-cancer therapies. Despite being mainly designed to act by inhibiting functional tumour antigens, there is increasing evidence that Fc-mediated engagement of the immune system is an important contributor to the efficacy of several of these therapies. The optimisation of this engagement offers the potential not only to augment efficacy against existing targets, but also to exploit non-functional tumour antigens. Antibodies that achieve efficacy wholly or predominantly through Fc-mediated mechanisms, represent rich opportunities for future therapeutics in oncology. This mini review summarises some of the key challenges, which need to be addressed to select the most effective molecules. These include the identification of optimal antibody characteristics and improvement of the drug discovery process, in particular, the relevance and predictive power of existing in vitro and in vivo screening methods. Advances in our understanding of tumour immunobiology and successful application of technologies designed to enhance immune system engagement will further aid this process.

show abstract

Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective

Cited by 127 publications

References 89 publications

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

Contact Info

Product

Resources

About