The von Willebrand A (VWA) domain is a well-studied domain involved in cell adhesion, in extracellular matrix proteins, and in integrin receptors. A number of human diseases arise from mutations in...

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Distribution and Evolution of von Willebrand/Integrin A Domains: Widely Dispersed Domains with Roles in Cell Adhesion and Elsewhere

The present invention relates to molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds FcγRIIIA and/or FcγRIIA with a greater affinity, relative to a comparable molecule comprising the wild-type Fc region. The molecules of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection. The molecules of the invention are particularly useful for the treatment or prevention of a disease or disorder where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by FcγR is desired, e.g., cancer, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.

IDENTIFICATION AND ENGINEERING OF ANTIBODIES WITH VARIANT Fc REGIONS AND METHODS OF USING SAME

Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector molecules to which their constant regions (Fc domains) engage. Thus, the antibody's Fc domain mediates diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the two dominant conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. Here we discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.

Type I and type II Fc receptors regulate innate and adaptive immunity

Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

https://www.meningitisamc.nl/en/about-us/publications/?download=13

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Mouse and human FcRs have been a major focus of attention not only of the scientific community, through the cloning and characterization of novel receptors, and of the medical community, through the identification of polymorphisms and linkage to disease but also of the pharmaceutical community, through the identification of FcRs as targets for therapy or engineering of Fc domains for the generation of enhanced therapeutic antibodies. The availability of knockout mouse lines for every single mouse FcR, of multiple or cell-specific--'a la carte'--FcR knockouts and the increasing generation of hFcR transgenics enable powerful in vivo approaches for the study of mouse and human FcR biology. This review will present the landscape of the current FcR family, their effector functions and the in vivo models at hand to study them. These in vivo models were recently instrumental in re-defining the properties and effector functions of FcRs that had been overlooked or discarded from previous analyses. A particular focus will be made on the (mis)concepts on the role of high-affinity IgG receptors in vivo and on results from antibody engineering to enhance or abrogate antibody effector functions mediated by FcRs.

https://www.umassmed.edu/globalassets/immunology-and-microbiology/documents/papers-for-bbs821-2015/nov-19-fcreceptorsbruhns_et_al-2015-immunological_reviews.pdf

Mouse and human FcR effector functions.

Development of anti-Fas Abs to treat diseases with insufficient Fas-mediated apoptosis has been limited by concern about hepatotoxicity. We report here that hepatotoxicity elicited by anti-Fas Ab Jo2 is dependent on FcgammaRIIB. Thus, following Jo2 treatment, all FcgammaRIIB(-/-) mice survived while 80% of wild-type and all FcR-gamma(-/-) mice died from acute liver failure. Microscopic examination suggests that FcgammaRIIB deficiency protects the hepatic sinusoidal endothelium, a cell type that normally coexpresses Fas and FcgammaRIIB. In vitro studies showed that FcgammaRIIB, but not FcgammaRI and FcgammaRIII, on neighboring macrophages substantially enhanced Jo2 mediated apoptosis of Fas expressing target cells. However, FcgammaRI and FcgammaRIII appeared essential for apoptosis-inducing activity of a non-hepatotoxic anti-Fas mAb HFE7A. These findings imply that by interacting with the Fc region of agonistic Abs, FcgammaRs can modulate both the desired and undesired consequences of Ab-based therapy. Recognizing this fact should facilitate development of safer and more efficacious agonistic Abs.

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FcγRs Modulate Cytotoxicity of Anti-Fas Antibodies: Implications for Agonistic Antibody-Based Therapeutics

Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2−/−), CR3 (CR3−/−), or CR4 (CR4−/−) were challenged with WU2, a PspA+ capsular serotype 3 pneumococcus, and its PspA− mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD−/−), LFA-1-deficient (LFA-1−/−), and CD18-deficient (CD18−/−) mice. We found that FD−/−, CR3−/−, and CR4−/− mice had significantly decreased longevity and survival rate upon infection with WU2. In comparison, PspA− pneumococci were virulent only in FD−/− and CR1/2−/− mice. Normal mouse serum supported more C3 deposition on pneumococci than FD−/− serum, and more iC3b was deposited onto the PspA− than the PspA+ strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against pneumococcal infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CR3, and CR4 all play important roles in host defense against pneumococcal infection.

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The virulence function of Streptococcus pneumoniae surface protein a involves inhibition of complement activation and impairment of complement receptor-mediated protection

The interaction of factor B with C3b deposited on the surface of pathogens is the first step in the activation of the alternative complement pathway. The role of the von Willebrand factor type A (VWFA) module of factor B in this interaction has been investigated by generating three chimeras, Ch1-Ch3, in which surface loops of the VWFA module flanking the cation-binding residues were replaced by the corresponding sequences of C2, a factor B-like molecule which does not bind C3b. The location of the three loops was inferred from a homology model based on the structure of the integrin alphaM VWFA module [Ch1, betaA-alpha1 loop: Ch2, alpha3-alpha4 loop; and Ch3, betaD-alpha5 loop; Lee, J.-O., et al. (1995b) Cell 80, 631-638]. The function of the chimeras was studied by means of hemolytic assays and assays of the individual steps of the alternative complement pathway, i.e., binding to the C3b analogue cobra venom factor and factor D cleavage. These experiments showed that Ch1 and Ch3 define regions that are involved in C3b binding whereas Ch2 does not appear to be involved in binding specificity. The inability of Ch1 to register the enhancement of cobra venom factor binding normally seen after factor D cleavage suggested that the betaA-alpha1 loop mediates the conformational regulation of ligand binding affinity. Homology modeling of the chimeras has been used to visualize the surface structures which potentially define the C3b binding site.

Yuanyuan Xu

Papers

FcγRs Modulate Cytotoxicity of Anti-Fas Antibodies: Implications for Agonistic Antibody-Based Therapeutics

The virulence function of Streptococcus pneumoniae surface protein a involves inhibition of complement activation and impairment of complement receptor-mediated protection

Surface loops adjacent to the cation-binding site of the complement factor B von Willebrand factor type A module determine C3b binding specificity

Activation of the alternative complement pathway in factor D-deficient mice