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1.
Elife ; 122023 Dec 21.
Article in English | MEDLINE | ID: mdl-38127423

ABSTRACT

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here, we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.


Subject(s)
Abatacept , B-Lymphocytes , T-Lymphocytes, Regulatory , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Abatacept/pharmacology , Animals , Mice , CTLA-4 Antigen/genetics , CTLA-4 Antigen/immunology , Lymphocyte Depletion , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Apoptosis/drug effects , Immunoglobulins/blood , Immunoglobulins/immunology , CHO Cells , Cricetulus , Mice, Inbred C57BL , Male , Female
2.
Sci Transl Med ; 15(685): eabm5663, 2023 03.
Article in English | MEDLINE | ID: mdl-36857433

ABSTRACT

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.


Subject(s)
Immune Checkpoint Inhibitors , Immunotherapy , Humans , Abatacept , Ipilimumab , Nivolumab
3.
bioRxiv ; 2023 Aug 29.
Article in English | MEDLINE | ID: mdl-36909522

ABSTRACT

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here we probe the decline of B cells in human CTLA-4 knock-in mice by using antihuman CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

5.
Cell Res ; 29(8): 609-627, 2019 08.
Article in English | MEDLINE | ID: mdl-31267017

ABSTRACT

It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , CTLA-4 Antigen/metabolism , Immunotherapy/adverse effects , Ipilimumab/therapeutic use , Lysosomes/metabolism , Neoplasms/therapy , Proteolysis/drug effects , Animals , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/pharmacology , CHO Cells , CTLA-4 Antigen/genetics , CTLA-4 Antigen/immunology , Cricetulus , Gene Knock-In Techniques , HEK293 Cells , Humans , Hydrogen-Ion Concentration , Immunoglobulin G/pharmacology , Immunoglobulin G/therapeutic use , Ipilimumab/adverse effects , Ipilimumab/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocytes, Regulatory/immunology , Transfection
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