Streptococcal IdeS and Its Impact on Immune Response and Inflammation

Pawel‐Rammingen, Ulrich von

doi:10.1159/000332940

Cited by 36 publications

(23 citation statements)

References 108 publications

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“…Pertinent to the concept of in vivo proteolysis of IgGs was the finding that a coadministration of IdeS proteinase with trastuzumab totally abolished antitumor efficacy in the BT474 mouse xenograft model. This finding verified the potent IgG cleavage activity of IdeS and the in vivo consequences of IgG functional impairment by this proteinase and potentially others with relevance to cancer (35).…”

Section: Discussionsupporting

confidence: 76%

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Fan

Brezski

Deng

et al. 2015

Molecular Cancer Therapeutics

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Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity.

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Section: Discussionsupporting

confidence: 76%

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Fan

Brezski

Deng

et al. 2015

Molecular Cancer Therapeutics

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“…Two study groups independently identified a non-SpeB protease with efficient IgG-degrading activity and a secreted protein with homology to the α-subunit of human Mac-1 (CD11b/CD18, CR3), resulting in the IdeS/Mac-1 nomenclature [43, 44]. IdeS/Mac-1 is a 35-kDa cysteine endopeptidase with strict specificity to IgG and is present in all strains in 1 of 2 allelic variants [45]. IdeS/Mac-1 interaction with IgG results in proteolytic cleavage at a specific site present in the lower region of the heavy chain between 2 glycine residues (G236 and G237), efficiently inhibiting complement-binding and Fc recognition (Fig.…”

Section: Secreted Complement Evasins Of Gasmentioning

confidence: 99%

“…2 (B)) [44]. Hydrolysis of streptococcal IgG antibodies by IdeS/Mac-1 produces high amounts of circulating F(ab’) 2 fragments, which can rebind to the bacterial surface but cannot mediate complement activation or immune cell signaling, thus exerting a protective effect [45]. IdeS/Mac-1 also contains an Arg-Gly-Asp (RGD) motif, a sequence commonly associated with integrin binding.…”

Section: Secreted Complement Evasins Of Gasmentioning

confidence: 99%

Catch Me if You Can: <b><i>Streptococcus pyogenes</i></b> Complement Evasion Strategies

Laabei¹,

Ermert²

2018

J Innate Immun

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The human host has evolved elaborate protection mechanisms to prevent infection from the billions of microorganisms to which it host is exposed and is home. One of these systems, complement, is an evolutionary ancient arm of innate immunity essential for combatting bacterial infection. Complement permits the efficient labelling of bacteria with opsonins, supports phagocytosis, and facilitates phagocyte recruitment to the site of infection through the production of chemoattractants. However, it is by no means perfect, and certain organisms engage in an evolutionary arms race with the host where complement has become a major target to promote immune evasion. Streptococcus pyogenes is a major human pathogen that causes significant morbidity and mortality globally. S. pyogenes is also a member of an elite group of bacterial pathogens possessing a sophisticated arsenal of virulence determinants capable of interfering with complement. In this review, we focus on these complement evasins, their mechanism of action, and their importance in disease progression. Finally, we highlight new therapeutic options for fighting S. pyogenes, by interfering with one of its main mechanisms of complement evasion.

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“…2 Proteases associated with cancer, inflammation, and infectious diseases are represented in the group. 3,4 These autoantibodies also bind to single-chain peptide analogs of the IgG1 hinge possessing defined C-termini that correspond to sites generated in IgG by protease action. 2,5 Comparable autoimmune profiles were not detected against the hinge region of intact IgG 2 or to cleavage site analog peptides with the opposing free N-termini.…”

Section: Introductionmentioning

confidence: 99%

A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo

Brezski

Kinder

Grugan

et al. 2014

mAbs

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We report a chimeric monoclonal antibody (mAb) directed to a neo-epitope that is exposed in the IgG lower hinge following proteolytic cleavage. The mAb, designated 2095-2, displays specificity for IdeS-generated F(ab')₂ fragments, but not for full-length IgG or for closely-related F(ab')₂ fragments generated with other proteases. A critical component of the specificity is provided by the C-terminal amino acid of the epitope corresponding to gly-236 in the IgG1 (also IgG4) hinge. By its ability to bind to IdeS-cleaved anti-CD20 mAb, mAb 2095-2 fully restored antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against WIL2-S cells to the otherwise inactive anti-CD20 IgG1 F(ab')₂ fragment. Similarly, 2095-2 reinstated ADCC against MDA-MB-231 cells to an anti-CD142 IgG1 F(ab')₂ fragment. mAb 2095-2 was also capable of eliciting both CDC and ADCC to IgG4 F(ab')₂ fragments, an IgG subclass that has weaker ADCC and CDC when intact relative to intact IgG1. The in vitro cell-based efficacy of 2095-2 was extended to the in vivo setting using platelets as a cell clearance surrogate. In a canine model, the co-administration of 2095-2 together with IdeS-generated, platelet-targeting anti-CD41/61 F(ab')₂ fragment not only restored platelet clearance, but did so at a rate and extent of clearance that exceeded that of intact anti-CD41/61 IgG at comparable concentrations. To further explore this unexpected amplification effect, we conducted a rat study in which 2095-2 was administered at a series of doses in combination with a fixed dose of anti-CD41/61 F(ab')₂ fragments. Again, the combination, at ratios as low as 1:10 (w/w) 2095-2 to F(ab')₂, proved more effective than the anti-CD41/61 IgG1 alone. These findings suggest a novel mechanism for enhancing antibody-mediated cell-killing effector functions with potential applications in pathologic settings such as tumors and acute infections where protease activity is abundant.

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Streptococcal IdeS and Its Impact on Immune Response and Inflammation

Cited by 36 publications

References 108 publications

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies

Catch Me if You Can: <b><i>Streptococcus pyogenes</i></b> Complement Evasion Strategies

A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo

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