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1.
Proc Natl Acad Sci U S A ; 115(4): E733-E742, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29311317

RESUMO

Protein-based drugs are very active in treating cancer, but their efficacy can be limited by the formation of neutralizing antidrug antibodies (ADAs). Recombinant immunotoxins are proteins that are very effective in patients with leukemia, where immunity is suppressed, but induce ADAs, which compromise their activity, in patients with intact immunity. Here we induced a specific, durable, and transferable immune tolerance to recombinant immunotoxins by combining them with nanoparticles containing rapamycin (SVP-R). SVP-R mitigated the formation of inhibitory ADAs in naïve and sensitized mice, resulting in restoration of antitumor activity. The immune tolerance is mediated by colocalization of the SVP-R and immunotoxin to dendritic cells and macrophages in the spleen and is abrogated by depletion of regulatory T cells. Tolerance induced by SVPs was not blocked by checkpoint inhibitors or costimulatory agonist monoclonal antibodies that by themselves enhance ADA formation.


Assuntos
Imunomodulação , Imunossupressores/administração & dosagem , Imunotoxinas/administração & dosagem , Leucemia/terapia , Sirolimo/administração & dosagem , Animais , Anticorpos Neutralizantes , Proteínas Ligadas por GPI/imunologia , Humanos , Imunotoxinas/imunologia , Mesotelina , Nanopartículas , Fatores de Tempo
2.
Vet Sci ; 5(4)2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30563208

RESUMO

Infusions with immune cells, such as lymphocytes or natural killer (NK) cells, represent one of several modalities of immunotherapy. In human patients with advanced B-cell leukemia or lymphoma, infusions with chimeric antigen receptor (CAR) T-lymphocytes have shown promising responses. However, the scientific and clinical development of cell-based therapies for dogs, who get cancer of similar types as humans, is lagging behind. One reason is that immune cells and their functionality in dogs are less well characterized, largely due a lack of canine-specific reagents to detect surface markers, and specific cytokines to isolate and expand their immune cells. This review summarizes the current status of canine cancer immunotherapies, with focus on autologous and allogeneic T-lymphocytes, as well as NK cells, and discusses potential initiatives that would allow therapies with canine immune cells to "catch up" with the advances in humans.

3.
Cell Mol Immunol ; 14(5): 432-442, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-26477977

RESUMO

Antibodies against the toxin portion of recombinant immunotoxins (RIT) reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SS1P to produce LMB-T20, a de-immunized RIT that has the eight human T-cell epitopes in SS1P modified or removed. To determine the effect of T-cell epitope removal in vivo we mapped the T-cell epitopes in immune-competent BALB/c mice and found that these mice recognize two epitopes. One corresponds to the human immunodominant T-cell epitope and the other to a human subdominant epitope; both were eliminated in LMB-T20. We found that mice immunized with LMB-T20 did not have T-cell activation and did not develop anti-drug antibodies (ADA), whereas mice immunized with SS1P, showed T-cell activation, and developed ADA detected by both ELISA and drug neutralizing assays. The ability of the mice treated with LMB-T20 to respond to other antigens was not compromised. We conclude that elimination of T-cell epitopes is sufficient to prevent formation of antibodies to an immunogenic foreign protein.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos/imunologia , Formação de Anticorpos/imunologia , Epitopos de Linfócito T/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Feminino , Humanos , Imunização , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C
4.
AAPS J ; 19(1): 117-129, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27796910

RESUMO

Identification of helper T-cell epitopes is important in many fields of medicine. We previously used an experimental approach to identify T-cell epitopes in PE38, a truncated bacterial toxin used in immunotoxins. Here, we evaluated the ability of antibodies to DR, DP, or DQ to block T-cell responses to PE38 epitopes in 36 PBMC samples. We predicted the binding affinities of peptides to DR, DP, and DQ alleles using computational tools and analyzed their ability to predict the T-cell epitopes. We found that HLA-DR is responsible for 65% of the responses, DP 24%, and DQ 4%. One epitope that is presented in 20% of the samples (10/50) is entirely DP restricted and was not predicted to bind to DR or DP reference alleles using binding algorithms. We conclude that DP has an important role in helper T-cell response to PE38.


Assuntos
Toxinas Bacterianas/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-DP/química , Imunotoxinas/imunologia , Peptídeos/química , Algoritmos , Alelos , Sequência de Aminoácidos , Sítios de Ligação , Células Cultivadas , Epitopos de Linfócito T/genética , Citometria de Fluxo , Genes MHC da Classe II , Antígenos HLA-DP/genética , Antígenos HLA-DP/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Peptídeos/imunologia
5.
Oncotarget ; 7(21): 29916-26, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27167198

RESUMO

Recombinant immunotoxins (RITs) are genetically engineered proteins being developed to treat cancer. They are composed of an Fv that targets a cancer antigen and a portion of a protein toxin. Their clinical success is limited by their immunogenicity. Our goal is to produce a new RIT that targets mesothelin and is non-immunogenic by combining mutations that decrease B- and T-cell epitopes. Starting with an immunotoxin that has B-cell epitopes suppressed, we added mutations step-wise that suppress T-cell epitopes. The final protein (LMB-T14) has greatly reduced antigenicity as assessed by binding to human anti-sera and a greatly decreased ability to activate helper T-cells evaluated in a T-cell activation assay. It is very cytotoxic to mesothelioma cells from patients, and to cancer cell lines. LMB-T14 produces complete remissions of a mesothelin expressing cancer (A431/H9) xenograft. The approach used here can be used to de-immunize other therapeutic foreign proteins.


Assuntos
Proteínas Ligadas por GPI/antagonistas & inibidores , Imunotoxinas/imunologia , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Proteínas Recombinantes de Fusão/imunologia , Imunidade Adaptativa , Animais , Anticorpos Monoclonais/imunologia , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Linhagem Celular Tumoral , Epitopos de Linfócito B/genética , Epitopos de Linfócito T/genética , Exotoxinas/genética , Exotoxinas/imunologia , Feminino , Humanos , Região Variável de Imunoglobulina/imunologia , Imunoterapia/métodos , Imunotoxinas/genética , Imunotoxinas/uso terapêutico , Neoplasias Pulmonares/imunologia , Mesotelina , Mesotelioma/imunologia , Mesotelioma Maligno , Camundongos , Camundongos Nus , Terapia de Alvo Molecular/métodos , Mutação , Engenharia de Proteínas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T Auxiliares-Indutores , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Cancer Ther ; 14(12): 2789-96, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26443804

RESUMO

SS1P is a recombinant immunotoxin (RIT) that targets mesothelin. It consists of an antimesothelin Fv fused to a portion of Pseudomonas exotoxin A. In clinical studies, it has produced dramatic responses in patients with advanced mesothelioma, when combined with immunosuppressive therapy so that several treatment cycles could be given. Otherwise its activity is limited by its immunogenicity. In this work, we describe the development and characterization of LMB-T20, a highly potent RIT targeted at mesothelin-expressing cancers with low immunogenicity due to removal of its eight T-cell epitopes. LMB-T20 was more active than SS1P when tested on four different mesothelin-expressing cell lines as well as on cells obtained from patients with mesothelioma. It also has potent antitumor activity in mice, and has reduced immunogenicity as measured by cytokine secretion assays. In conclusion, LMB-T20 is a favorable candidate for evaluation in clinical trials due to its reduced immunogenicity and excellent activity.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Epitopos de Linfócito T/imunologia , Proteínas Ligadas por GPI/imunologia , Mesotelioma/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , ADP Ribose Transferases/genética , ADP Ribose Transferases/imunologia , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Linhagem Celular Tumoral , Epitopos de Linfócito T/genética , Exotoxinas/genética , Exotoxinas/imunologia , Proteínas Ligadas por GPI/biossíntese , Humanos , Fenômenos Imunogenéticos/efeitos dos fármacos , Mesotelina , Mesotelioma/genética , Mesotelioma/imunologia , Camundongos , Mutação , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Fatores de Virulência/genética , Fatores de Virulência/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Exotoxina A de Pseudomonas aeruginosa
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