scholarly journals APX005M, a CD40 agonist antibody with unique epitope specificity and Fc receptor binding profile for optimal therapeutic application

2021 ◽  
Author(s):  
Erin L. Filbert ◽  
Pia K. Björck ◽  
Minu K. Srivastava ◽  
Frances R. Bahjat ◽  
Xiaodong Yang
Keyword(s):  
Cd40 Ligand ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Fcγ Receptors ◽  
Potent Inducer ◽  
Immune Effector ◽  
Effector Functions ◽  
Adaptive Immune ◽  
Epitope Specificity ◽  
Agonist Antibody ◽  
Favorable Safety

AbstractTargeting CD40 with agonist antibodies is a promising approach to cancer immunotherapy. CD40 acts as a master regulator of immunity by mobilizing multiple arms of the immune system to initiate highly effective CD8 + T-cell-mediated responses against foreign pathogens and tumors. The clinical development of CD40 agonist antibodies requires careful optimization of the antibody to maximize therapeutic efficacy while minimizing adverse effects. Both epitope specificity and isotype are critical for CD40 agonist antibody mechanism of action and potency. We developed a novel antibody, APX005M, which binds with high affinity to the CD40 ligand-binding site on CD40 and is optimized for selective interaction with Fcγ receptors to enhance agonistic potency while limiting less desirable Fc-effector functions like antibody-dependent cellular cytotoxicity of CD40-expressing immune cells. APX005M is a highly potent inducer of innate and adaptive immune effector responses and represents a promising CD40 agonist antibody for induction of an effective anti-tumor immune response with a favorable safety profile.

Dendritic cells and T cells in rheumatoid arthritis

2020 ◽  
pp. 73-84
Author(s):  
Soi-Cheng Law ◽  
Pascale Wehr ◽  
Harriet Purvis ◽  
Ranjeny Thomas
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Dendritic Cells ◽  
Autoimmune Response ◽  
Immune Effector ◽  
Effector Functions ◽  
Adaptive Immune ◽  
Cell Antibody ◽  
Innate Immune Effector ◽  
Antigen Presenting

Dendritic cells (DCs) are specialized antigen-presenting cells which link the innate and adaptive immune responses, activating and priming effector CD4+ T cells, cross-presenting antigen to CD8+ T cells, and promoting B-cell antibody production. DCs also play important roles in the maintenance of immune tolerance. DCs and T cells underpin the basis of the autoimmune response in rheumatoid arthritis. In this chapter we describe the function of DCs and the response of T cells in rheumatoid arthritis pathogenesis, introduce the DC and T-cell players and their function in the immune system, then review the evidence for their involvement in the pathogenesis of rheumatoid arthritis (RA), particularly through the presentation of antigen that triggers the differentiation of autoreactive T cells, as well as innate immune effector functions. Finally, the emerging prospects for DC targeting for immunotherapy are covered.

scholarly journals There Is Strength in Numbers: Quantitation of Fc Gamma Receptors on Murine Tissue-Resident Macrophages

2021 ◽  
Vol 22 (22) ◽  
pp. 12172
Author(s):  
Christof Vorsatz ◽  
Niklas Friedrich ◽  
Falk Nimmerjahn ◽  
Markus Biburger
Keyword(s):  
Immune Complexes ◽  
Expression Patterns ◽  
Fcγ Receptors ◽  
Immune Effector ◽  
Effector Cells ◽  
Effector Functions ◽  
Immune Effector Cells ◽  
Innate Immune Effector ◽  
Murine Liver ◽  
Murine Tissue

Many of the effector functions of antibodies rely on the binding of antibodies/immune complexes to cellular Fcγ receptors (FcγRs). Since the majority of innate immune effector cells express both activating and inhibitory Fc receptors, the outcome of the binding of immune complexes to cells of a given population is influenced by the relative affinities of the respective IgG subclasses to these receptors, as well as by the numbers of activating and inhibitory FcγRs on the cell surface. A group of immune cells that has come into focus more recently is the various subsets of tissue-resident macrophages. The central functions of FcγRs on tissue macrophages include the clearance of opsonized pathogens, the removal of small immune complexes from the circulation and the depletion of antibody-opsonized cells in the therapy of autoimmunity and cancer. Despite these essential functions of FcγRs on tissue-resident macrophages, an in-depth quantification of FcγRs is lacking. Thus, the aim of our current study was to quantify the various Fcγ receptors on macrophages in murine liver, lung, kidney, brain, skin and spleen. Our study identified a pronounced heterogeneity between FcγR expression patterns of the different tissue macrophages, which may reflect their specialized functions within their unique niches in different organ environments.

scholarly journals Decay of Fc-dependent antibody functions after mild to moderate COVID-19

2020 ◽  
Author(s):  
Wen Shi Lee ◽  
Kevin John Selva ◽  
Samantha K. Davis ◽  
Bruce D. Wines ◽  
Arnold Reynaldi ◽  
...  
Keyword(s):  
Immune Cells ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Neutralising Antibodies ◽  
Specific Antibodies ◽  
Effector Functions ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Specific Igg ◽  
Serial Samples ◽  
Over Time

AbstractThe capacity of antibodies to engage with innate and adaptive immune cells via the Fc region is important in preventing and controlling many infectious diseases, and is likely critical in SARS-CoV-2 infection. The evolution of such antibodies during convalescence from COVID-19 is largely unknown. We developed novel assays to measure Fc-dependent antibody functions against SARS-CoV-2 spike (S)-expressing cells in serial samples from a cohort of 53 subjects primarily with mild-moderate COVID-19, out to a maximum of 149 days post-infection. We found that S-specific antibodies capable of engaging dimeric FcγRIIa and FcγRIIIa decayed linearly over time. S-specific antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP) activity within plasma declined linearly as well, in line with the decay of S-specific IgG. Although there was significant decay in S-specific plasma ADCC and ADP activity, they remained readily detectable by all assays in 94% of our cohort at the last timepoint studied, in contrast with neutralisation activity which was only detectable in 70% of our cohort by the last timepoint. Our results suggest that Fc effector functions such as ADCC and ADP could contribute to the durability of SARS-CoV-2 immunity, particularly late in convalescence when neutralising antibodies have waned. Understanding the protective potential of antibody Fc effector functions is critical for defining the durability of immunity generated by infection or vaccination.

scholarly journals Understudied Factors Influencing Fc-Mediated Immune Responses against Viral Infections

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 103 ◽  
Author(s):  
Sai Priya Anand ◽  
Andrés Finzi
Keyword(s):  
Viral Replication ◽  
Viral Infections ◽  
Viral Glycoprotein ◽  
Immune Effector ◽  
Effector Functions ◽  
Adaptive Immune ◽  
Cell Clearance ◽  
Innate Immune Effector ◽  
Infected Cells ◽  
Adaptive Immune Systems

Antibodies play a crucial role in host defense against viruses, both by preventing infection and by controlling viral replication. Besides their capacity to neutralize viruses, antibodies also exert their antiviral effects by crystallizable fragment (Fc)-mediated effector mechanisms. This involves a bridge between innate and adaptive immune systems, wherein antibodies form immune complexes that drive numerous innate immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent complement-mediated lysis, and antibody-dependent phagocytosis. Here, we review certain mechanisms that modulate these antibody-mediated effector functions against virally infected cells, such as viral glycoprotein shedding, viral glycoprotein internalization, antibody cooperativity, and antibody glycosylation. These mechanisms can either protect viral replication or enhance infected cell clearance. Here we discuss the importance of these understudied factors in modulating Fc-mediated effector functions.

scholarly journals Fc-engineered antibodies with immune effector functions completely abolished

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260954
Author(s):  
Ian Wilkinson ◽  
Stephen Anderson ◽  
Jeremy Fry ◽  
Louis Alex Julien ◽  
David Neville ◽  
...  
Keyword(s):  
Fusion Proteins ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Therapeutic Antibodies ◽  
Fcγ Receptors ◽  
Specific Amino Acid ◽  
Immune Effector ◽  
Effector Functions ◽  
Cytokine Responses ◽  
Novel Variants

Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been described in the literature but none of them completely eliminates binding to all of the Fcγ receptors. Here we describe a set of novel variants having specific amino acid substitutions in the Fc region at L234 and L235 combined with the substitution G236R. They show no detectable binding to Fcγ receptors or to C1q, are inactive in functional cell-based assays and do not elicit inflammatory cytokine responses. Meanwhile, binding to FcRn, manufacturability, stability and potential for immunogenicity are unaffected. These variants have the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.

scholarly journals A functional spleen contributes to afucosylated IgG in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iwona Wojcik ◽  
David E. Schmidt ◽  
Lisa A. de Neef ◽  
Minke A. E. Rab ◽  
Bob Meek ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Infections ◽  
Immune Cell ◽  
Lymphoid Organ ◽  
Immune Effector ◽  
Adaptive Immune ◽  
Wide Range ◽  
Humoral Responses ◽  
First Time

AbstractAs a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.

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