Modification of the Fc Region of a Primatized IgG Antibody to Human CD4 Retains Its Ability to Modulate CD4 Receptors but Does Not Deplete CD4+ T Cells in Chimpanzees

Newman, Roland; Hariharan, Kandasamy; Reff, Mitchell E.; Anderson, Darrel R.; Braslawsky, Gary R.; Santoro, Denise; Hanna, Nabil; Bugelski, Peter J.; Brigham-Burke, Michael; Crysler, Carl; Gagnon, Robert; Monte, Paul Dal; Doyle, Michael L.; Hensley, Preston; Reddy, Manjula; Sweet, Raymond W.; Truneh, Alemseged

doi:10.1006/clim.2000.4975

Cited by 53 publications

(33 citation statements)

References 33 publications

(40 reference statements)

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“…This induction can be decreased by changing two amino acids in the CH2 domain (F234A and L235A) where the interaction with FcγRIII is reported. [9][10][11][12] The effector function potential of IgG1 isotypes can also be modified. In cases where decreased effector function is wanted, mutations in CH 2 , similar to those made in the above IgG4s can decrease the effector function of IgG1 antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple reports demonstrate that in certain cases IgG4s can induce ADCC. [10][11][12]40 The affinity engineered anti-CD20 antibody is capable of inducing ADCC as an IgG4 isotype antibody (either as a wild type IgG4 or as a stability engineered S > P variant) as measured by the PBMC based assay. This low level activity is also observed in the ADCC-reporter assay (Fig.…”

Section: © 2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

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Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay

Parekh

Berger

Sibley

et al. 2012

mAbs

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Section: Resultsmentioning

confidence: 99%

Section: © 2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay

Parekh

Berger

Sibley

et al. 2012

mAbs

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“…The single amino acid exchange of leucine for glutamic acid at position 235 (EU numbering system) (14) on the border of the hinge and CH2 region has been shown to reduce Fc-mediated effector function through elimination of binding to FcgR (15,29,30). We sought to test the hypothesis that in cocultures, FcFcgR interactions (e.g., involving monocytes) might provide a physiological equivalent to immobilization on plastic, bringing about cross-linking of CD28 or mimicking synapse formation or triggering FcgR-mediated secondary effects that may stimulate PBMCs to secrete cytokines, and explaining the requirement for the Fc region.…”

Section: Responses Of Pbmcs To Nib(28sa)-g4 Nib(28sa)-g1 and Nib(28mentioning

confidence: 99%

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

Ball

Fox

Hufton

et al. 2012

The Journal of Immunology

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The unexpected outcome of the clinical trial of the superagonistic CD28 mAb TGN1412 (IgG4κ) continues to stimulate interest. We show that TGN1412 binds similarly to human and cynomolgus macaque FcγR, eliminating the possibility that differences in Fc-mediated interactions with FcγR contributed to the failure of preclinical testing in macaques to predict toxicity in humans. The influence of the Fc domain and C region structure on the in vitro functional activity of TGN1412 was investigated using F(ab′)2 and Fab fragments derived from TGN1412 recovered from the trial and recombinant TGN1412 subclass variants and mutants. Superagonistic activity, as measured by cytokine release and proliferation, was assessed by exposing PBMCs to immobilized mAbs/fragments or to aqueous mAbs/fragments in the presence of HUVEC monolayers. Removing the Fc generally curtailed or abolished PBMC activation. However, eliminating detectable FcγR-binding of the IgG4 by mutation (L235E) did not abrogate activity. Stabilizing the “wild-type” IgG4 hinge (S228P) enhanced activity without increasing FcγR binding, which could only partially be explained by inhibition of Fab arm–exchange. Subclass switching the IgG4 mAb to IgG1 decreased activity, whereas switching to IgG2 markedly increased activity. We conclude that the C region strongly influences in vitro CD28-mediated superagonistic signaling. Superagonism requires an intact Fc, as shown by the absence of activity of TGN1412 Fab and F(ab′)2 fragments, but, notably, appears to be relatively independent of FcγR-binding properties. We propose that the Fc, potentially through restricting flexibility, maintains a favorable V region conformation to allow superagonistic activity. These findings have important implications for Ab design strategies.

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“…Isotype control antibodies used in the study are IDEC-151, a primatized effectorless human IgG4PE antibody against CD4, with a P mutation in the hinge to convert the γ4 hinge to a γ1 hinge and an E mutation in CH2 to diminish binding to Fcγ receptors (40), and C2B8, a human-mouse chimeric IgG1 antibody specific to human CD20 (41). Both are from Biogen Idec.…”

Section: Antibodies and Cellsmentioning

confidence: 99%

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Dong

Demarest

Sereno

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer. Mol Cancer Ther; 9(9); 2593-604. ©2010 AACR.

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Modification of the Fc Region of a Primatized IgG Antibody to Human CD4 Retains Its Ability to Modulate CD4 Receptors but Does Not Deplete CD4+ T Cells in Chimpanzees

Cited by 53 publications

References 33 publications

Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay

Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

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