Fc-engineered antibodies with immune effector functions completely abolished

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.

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

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02814-2 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms222212172 ◽

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.

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Faculty Opinions recommendation of Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013028.190516 ◽

2003 ◽

Author(s):

Jeffrey Cohen

Keyword(s):

Human Cytomegalovirus ◽

Inflammatory Cytokine ◽

Toll Like Receptor ◽

Cytokine Responses ◽

Toll Like Receptor 2

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Interleukin-17A: A Potential Therapeutic Target in Chronic Lung Diseases

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190116115226 ◽

2019 ◽

Vol 19 (7) ◽

pp. 921-928 ◽

Cited By ~ 1

Author(s):

Sadiya Bi Shaikh ◽

Ashwini Prabhu ◽

Yashodhar Prabhakar Bhandary

Keyword(s):

Respiratory Diseases ◽

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Chronic Obstructive ◽

Interleukin 17 ◽

Potential Therapeutic Target ◽

Chronic Respiratory Diseases ◽

Chronic Lung Diseases ◽

Interleukin 17A ◽

Insight Into

Background: Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has gained a lot of attention because of its involvement in respiratory diseases. Interleukin-17 cytokine family includes six members, out of which, IL-17A participates towards the immune responses in allergy and inflammation. It also modulates the progression of respiratory disorders. Objective: The present review is an insight into the involvement and contributions of the proinflammatory cytokine IL-17A in chronic respiratory diseases like Idiopathic Pulmonary Fibrosis (IPF), Chronic Obstructive Pulmonary Distress (COPD), asthma, pneumonia, obliterative bronchiolitis, lung cancer and many others. Conclusion: IL-17A is a major regulator of inflammatory responses. In all the mentioned diseases, IL- 17A plays a prime role in inducing the diseases, whereas the lack of this pro-inflammatory cytokine reduces the severity of respective respiratory diseases. Thereby, this review suggests IL-17A as an instrumental target in chronic respiratory diseases.

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Leishmania donovani infection suppresses Allograft Inflammatory Factor-1 in monocytes and macrophages to inhibit inflammatory responses

Scientific Reports ◽

10.1038/s41598-020-79068-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ricardo Louzada da Silva ◽

Diana M. Elizondo ◽

Nailah Z. D. Brandy ◽

Naomi L. Haddock ◽

Thomas A. Boddie ◽

...

Keyword(s):

Immune Evasion ◽

Inflammatory Cytokine ◽

Leishmania Donovani ◽

Cytokine Production ◽

Inflammatory Responses ◽

Bone Marrow Cells ◽

Parasitic Infections ◽

Inflammatory Factor ◽

Immune Functions ◽

Inflammatory Cytokine Production

AbstractMacrophages and monocytes are important for clearance of Leishmania infections. However, immune evasion tactics employed by the parasite results in suppressed inflammatory responses, marked by deficient macrophage functions and increased accumulation of monocytes. This results in an ineffective ability to clear parasite loads. Allograft Inflammatory Factor-1 (AIF1) is expressed in myeloid cells and serves to promote immune responses. However, AIF1 involvement in monocyte and macrophage functions during parasitic infections has not been explored. This study now shows that Leishmania donovani inhibits AIF1 expression in macrophages to block pro-inflammatory responses. Mice challenged with the parasite had markedly reduced AIF1 expression in splenic macrophages. Follow-up studies using in vitro approaches confirmed that L. donovani infection in macrophages suppresses AIF1 expression, which correlated with reduction in pro-inflammatory cytokine production and increased parasite load. Ectopic overexpression of AIF1 in macrophages provided protection from infection, marked by robust pro-inflammatory cytokine production and efficient pathogen clearance. Further investigations found that inhibiting AIF1 expression in bone marrow cells or monocytes impaired differentiation into functional macrophages. Collectively, results show that AIF1 is a critical regulatory component governing monocyte and macrophage immune functions and that L. donovani infection can suppress the gene as an immune evasion tactic.

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