Lysine 322 in the human IgG3 CH2 domain is crucial for antibody dependent complement activation

Thommesen, John Einar; Michaelsen, Terje E.; Løset, Geir Åge; Sandlie, Inger; Brekke, Ole Henrik

doi:10.1016/s0161-5890(01)00010-4

Cited by 64 publications

(50 citation statements)

References 35 publications

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“…In preliminary work, the K322A mutant was confirmed to have lost CDC activity as previously reported, 31,32 while the L234A/L235A mutant retained most of the activity (Fig. S1).…”

Section: Engineering Of Farletuzumab Mutantssupporting

confidence: 81%

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

Lin

Spidel

Maddage

et al. 2013

Cancer Biology & Therapy

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“…In preliminary work, the K322A mutant was confirmed to have lost CDC activity as previously reported, 31,32 while the L234A/L235A mutant retained most of the activity (Fig. S1).…”

Section: Engineering Of Farletuzumab Mutantssupporting

confidence: 81%

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

Lin

Spidel

Maddage

et al. 2013

Cancer Biology & Therapy

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“…6). This result is not surprising given the proximity of A330 to the C1q binding site (26,27). The set of S239D͞I332E and S239D͞I332E͞ A330L variants thus provide the option for enhancing ADCC in cases where CDC is desired or undesired.…”

Section: Designed Fc Variants Show Differential Capacity To Mediate Cmentioning

confidence: 91%

“…Interaction of Ab with complement is mediated by the protein C1q, the binding site for which is separate from but overlapping with the Fc␥R site (26,27). Alamar Blue release was used to monitor lysis of Fc variant and WT rituximab-opsonized CD20 ϩ target cells by human serum complement.…”

Section: Designed Fc Variants Show Differential Capacity To Mediate Cmentioning

confidence: 99%

Engineered antibody Fc variants with enhanced effector function

Lazar

Dang²,

Karki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

713

583

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Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fc␥ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fc␥ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.antibody-dependent cell-mediated cytotoxicity ͉ Fc␥R ͉ protein engineering ͉ cancer

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“…Lys B136 was selected as a residue from the apo plane, which is located near the bottom side of ghB and far away from any proposed binding site. (31)(32)(33)(34)(35). Chemical modification, mutational analysis, and molecular modeling approaches have been used to dissect the complementary IgG binding sites on the gC1q domain (7,10,11,19).…”

Section: Certain Key Residues Belonging To the Apo And Holo Planes Ofmentioning

confidence: 99%

Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains

et al. 2006

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C1q is the first subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the Cterminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has specific and differential binding properties toward C1q ligands. It is largely considered that C1q-ligand interactions are ionic in nature; however, the complementary ligand-binding sites on C1q and the mechanisms of interactions are still unclear. To identify the residues on the gC1q domain that are likely to be involved in ligand recognition, we have generated a number of substitution mutants of ghA, ghB, and ghC modules and examined their interactions with three selected ligands: IgG1, Creactive protein (CRP), and pentraxin 3 (PTX3). Our results suggest that charged residues belonging to the apex of the gC1q heterotrimer (with participation of all three chains) as well as the side of the ghB are crucial for C1q binding to these ligands, and their contribution to each interaction is different. It is likely that a set of charged residues from the gC1q surface participate † This study was supported by the National Science Foundation of Bulgaria, Grant MY-K-1303 to L.T.R. and L-1000 to M.S.K. R.G.is sponsored by the Deutsche Forschungsgemeinschaft through the Graduiertenkolleg GK370. U.K. is funded by the European Commission, University of Oxford, and the Alexander von Humboldt Foundation. A.M. and B.B. are funded by TELETHON, MIUR (FIRB Fund), the European Commission, and AIRC.© 2006 American Chemical Society * Corresponding author. Phone: +44-1865+44- -222325. Fax: +44-1865 +49-641-9941259. ukishore@hotmail.comu.kishore@rediffmail.com. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2013 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript via different ionic and hydrogen bonds with corresponding residues from the ligand, instead of forming separate binding sites. Thus, a recently proposed model suggesting the rotation of the gC1q domain upon ligand recognition may be extended to C1q interaction with CRP and PTX3 in addition to IgG1.C1q is the first subcomponent of the classical complement pathway and its binding to IgGor IgM-containing immune complexes leads to the autoactivation of C1r, which in turn, activates C1s. C1r and C1s, the two serine protease proenzymes, together with C1q constitute C1, the first component of the classical pathway. The activation of the C1 complex (C1q + C1r2 + C1s2) subsequently leads to the activation of the C2−C9 components of the classical pathway and the formation of the terminal-membrane-attack complex (MAC) (1, 2). C1q is a versatile innate immune molecule that can bind a diverse range of self and nonself ligands, ranging from proteins to lipids ...

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Lysine 322 in the human IgG3 CH2 domain is crucial for antibody dependent complement activation

Cited by 64 publications

References 35 publications

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

Engineered antibody Fc variants with enhanced effector function

Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains

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