Anti-carcinoembryonic Antigen Single-chain Variable Fragment Antibody Variants Bind Mouse and Human Neonatal Fc Receptor with Different Affinities That Reveal Distinct Cross-species Differences in Serum Half-life

Andersen, Jan Terje; Foss, Stian; Kenanova, Vania; Olafsen, Tove; Leikfoss, Ingvild Sørum; Roopenian, Derry C.; Wu, Anna M.; Sandlie, Inger

doi:10.1074/jbc.m112.355131

Cited by 31 publications

(33 citation statements)

References 54 publications

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“…22 This model can be used to test human IgGs 9,23 with the limitation that the overall mouse IgG level is strongly decreased. 24 Using this mouse model, in some cases a correlation between the PK of IgGs in primates, humans, and mice was observed. 22,25 Several studies were performed to investigate the in vitro affinity of various IgG formats from different species to FcRn molecules.…”

Section: Introductionmentioning

confidence: 87%

Characterization and screening of IgG binding to the neonatal Fc receptor

Neuber

Frese

Jaehrling³

et al. 2014

mAbs

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Section: Introductionmentioning

confidence: 87%

Characterization and screening of IgG binding to the neonatal Fc receptor

Neuber

Frese

Jaehrling³

et al. 2014

mAbs

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“…Vectors containing truncated versions of hFcgRI, hFcgRIIa, hFcgRIIb, hFcgRIIIa, and hFcgRIIIb cDNAs encoding their three ectodomains genetically fused to a cDNA encoding the Schistosoma japonicum glutathione S-transferase (GST) have been described (43,46). The vectors also contain a DNA segment corresponding to the EBV origin of replication (oriP).…”

Section: Production Of Hfcrn and Fcgrsmentioning

confidence: 99%

“…Alternatively, it may be desirable to tune the half-life to achieve intermediate or shorter persistence as a means to optimize the target/nontarget localization ratios of Abs used for tumor imaging. This can be accomplished by targeting Fc residues directly involved in binding to FcRn (I253, H310, and H435), and such IgG mutants have been shown to have a range of distinct half-life profiles (43,44). The positions of the amino acid residues are highlighted in the crystallographic illustrations of hIgG1 Fc shown in Fig.…”

mentioning

confidence: 99%

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Grevys

Bern

Foss

et al. 2015

The Journal of Immunology

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Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge–CH2 region, structurally distant from the binding site for FcRn at the CH2–CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn–IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants.

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“…A truncated cDNA segment encoding the extracellular domains of porcine FcRn (pFcRn) was synthesized by Genscript and subcloned into the pcDNA3-GST-hb2m-oriP vector using the restriction sites EcoRI and XhoI. Vectors encoding the ectodomains of human FcgRI, FcgRIIa, FcgRIIb, FcgRIIIa, and FcgRIIIb fused to GST have been described previously (34,35). All recombinant soluble receptors were produced by transient transfection of HEK293-EBNA cells, and secreted receptors were purified using a GSTrap column as described previously (34).…”

Section: Construction Production and Purification Of Recombinant Somentioning

confidence: 99%

Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation

Lau

Gunnarsen

Høydahl

et al. 2013

The Journal of Immunology

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CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14-mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases.

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Anti-carcinoembryonic Antigen Single-chain Variable Fragment Antibody Variants Bind Mouse and Human Neonatal Fc Receptor with Different Affinities That Reveal Distinct Cross-species Differences in Serum Half-life

Cited by 31 publications

References 54 publications

Characterization and screening of IgG binding to the neonatal Fc receptor

Characterization and screening of IgG binding to the neonatal Fc receptor

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation

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