Karen Manoutcharian

• PhD in Molecular Biology
• Principal Investigator at National Autonomous University of Mexico

In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine c...

While the antigenic variability is the major obstacle for developing vaccines against antigenically variable pathogens (AVPs) and cancer, this issue is not addressed adequately in current vaccine efforts. We developed a novel variable epitope library (VEL)-based vaccine strategy using immunogens carrying a mixture of thousands of variants of a sing...

The extreme antigenic variability of human immunodeficiency virus (HIV) leads to immune escape of the virus, representing a major challenge in the design of effective vaccine. We have developed a novel concept for immunogen construction based on introduction of massive mutations within the epitopes targeting antigenically variable pathogens and dis...

Despite the impressive impact of vaccines on public health, the success of vaccines targeting many important pathogens and cancers has to date been limited. The burden of infectious diseases today is mainly caused by antigenically variable pathogens (AVPs), which escape immune responses induced by prior infection or vaccination through changes in m...

Although various immune checkpoint inhibitors (ICIs), used for the treatment of advanced cancer, showed remarkably durable tumor regression in a subset of patients, there are important limitations in a large group of non-responders, and the generation of novel immunogens capable of inducing protective cellular immune responses is a priority in canc...

The employment of cancer vaccines as stand-alone or combined therapies has not yet reached clinically relevant endpoints in large clinical trials in the vast majority of patients, and there is a clear need for novel ideas and qualitatively new vaccine design approaches. In this study, we used a novel Variable Epitope Library (VEL) vaccine strategy,...

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Multiple genetic and environmental factors leading to progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) and consequent depletion of dopamine were described. Current clinical approaches, such as dopamine replacement or deep br...

Recombinant antibody fragments are promising alternatives to full-length immunoglobulins, creating big opportunities for the pharmaceutical industry. Nowadays, antibody fragments such as antigen-binding fragments (Fab), single-chain fragment variable (scFv), single-domain antibodies (sdAbs), and bispecific antibodies (bsAbs) are being evaluated as...

The development of recombinant antibody fragments as promising alternatives to full-length immunoglobulins offers vast opportunities for biomedicine. Antibody fragments have important advantages compared with conventional monoclonal antibodies that make them attractive for the biotech industry: superior stability and solubility, reduced immunogenic...

Breast cancer is one of the leading causes of death that affects the female population worldwide. Despite advances in treatments and a greater understanding of the disease, there are still difficulties in successfully treating patients. Currently, the main challenge in the field of cancer vaccines is antigenic variability which can reduce antigen-s...

Cancer is a set of related diseases of genetic origin characterised by a high genetic and/or antigenic variability. Identification of tumour-specific antigens is an attractive strategy employed in current personalised immunotherapies against cancer. Neoepitope-based vaccines have proved the efficacy of tumour-specific antigens in clinical trials. N...

The identification of novel targets for cancer immunotherapy and the development of new vaccine immunogens are subjects of permanent interest. MUC1 is an overexpressed antigen found in most tumors, and its overexpression correlates with poor prognosis. Many attempts to direct the immune response against MUC1 in tumor cells have failed, including se...

Resumen El cáncer es un conjunto de enfermedades relacionadas de origen genético que se caracterizan por una alta variabilidad genética y/o antigénica. La identificación de los antígenos específicos del tumor es una estrategia atractiva para el empleo de estos en las inmunoterapias personalizadas actuales contra el cáncer. Las vacunas de neoepítopo...

In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine c...

After decades of cancer vaccine efforts, there is an imperious necessity for novel ideas that may result in better tumor control in patients. We have proposed the use of a novel Variable Epitope Library (VEL) vaccine strategy, which incorporates an unprecedented number of mutated epitopes to target antigenic variability and break tolerance against...

Antibodies, T cell receptors and major histocompatibility complex molecules are members of the immunoglobulin superfamily and have pivotal roles in the immune system. The fine interrelation between them regulates several immune functions. Here, we describe lesser-known functions ascribed to these molecules in generating and maintaining immune respo...

Immune tolerance is the main challenge in the field of cancer vaccines, so modified peptide sequences or naturally occurring mutated versions of cancer‐related wild‐type (WT) antigens represent a promising pathway. However, the low immunogenicity of mutation‐induced neoantigens and, particularly, their incapacity to activate CD8⁺ T cells are genera...

Carbohydrate-binding modules (CBMs) are auxiliary domains into glycoside-hydrolases that allow the interaction between the insoluble substrate and the solubilized enzyme, through hydrophobic, CH-π interactions and hydrogen bonds. Here, we present the data article related to the interaction of one LaCBM26 and some mutated proteins with soluble α-glu...

GK-1 is a parasite-derived peptide adjuvant of 18 amino acid-length that enhances T-cell function and increases survival in B16-F10 melanoma tumor-bearing mice. This study was designed to evaluate in vivo the antitumor efficacy of GK-1 on 4T1 mouse mammary carcinoma. BALB/c mice with palpable primary tumors were weekly intravenously injected three...

Background Recombinant antibody fragments are promising alternatives to full-length immunoglobulins and offer important advantages compared with conventional monoclonal antibodies: extreme specificity, higher affinity, superior stability and solubility, reduced immuno-genicity as well as easy and inexpensive large-scale production. Objective In th...

White spot syndrome virus (WSSV) is the most important viral pathogen for the global shrimp industry causing mass mortalities with huge economic losses. Recombinant phages are capable of expressing foreign peptides on viral coat surface and act as antigenic peptide carriers bearing a phage-displayed vaccine. In this study, the full-length VP28 prot...

The antigenic variability of tumor cells leading to dynamic changes in cancer epitope landscape along with escape from immune surveillance by down-regulating tumor antigen expression/presentation and immune tolerance are major obstacles for the design of effective vaccines. We have developed a novel concept for immunogen construction based on intro...

Glioblastoma multiforme is the most frequent primary brain tumor, it has poor prognosis, and it remains refractory to current treatment. The success of temozolomide (TMZ) appears to be limited by the occurrence of chemoresistance. Recently, we report the use of pertussis toxin as adjuvant immunotherapy in a C6 glioma model; showing a decrease in tu...

Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious e...

The application of combinatorial approaches in conjunction with phage display techniques might be critical for development of vaccines against various infective and cancer diseases. Phage technique allows the generation of novel immunogens representing structural/molecular mimics of pathogen-derived immunodominant epitopes, or protein domains displ...

The application of combinatorial approaches in conjunction with phage display techniques might be critical for development of vaccines against various infective and cancer diseases. Phage technique allows the generation of novel immunogens representing structural/molecular mimics of pathogen-derived immunodominant epitopes, or protein domains displ...

Cysticercosis is a parasitic disease caused by Taenia solium which affects rurally bred pigs and humans in developing countries. The adult tapeworm parasite lives in the humans intestines, where it sheds thousands of eggs. Cysticercosis occurs after eggs are ingested by pigs or humans. In humans, cysticerci may cause neurocysticercosis, the most se...

This paper provides macroscopic and histological evidence on the statistically significant protective effects of S3Pvac-phage vaccination against porcine cysticercosis and hydatidosis. The study included 391 rustically bred pigs (187 vaccinated and 204 controls). Vaccination significantly reduced the prevalence of cysticercosis by 61.7%. Vaccinatio...

N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as animal models of AD, and represent highly desirable therapeutic targets. In the present study we have focused on N-truncated/modified Aβ peptide bearing amino-terminal pyroglutamate...

In this study, the authors have generated a tapeworm Taenia solium genomic DNA expression library where foreign peptides/proteins were fused to N-termini of M13 cpVIII and expressed at a high copy number on the phage surface, and they showed that this library may be used in bioselection against antipathogen immune sera, allowing the identification...

Anti-amyloid immunotherapy has been proposed as an appropriate therapeutic approach for Alzheimer's disease (AD). Significant efforts have been made towards the generation and assessment of antibody-based reagents capable of preventing and clearing amyloid aggregates as well as preventing their synaptotoxic effects. In this study, we selected a nov...

N-truncated and N-modified forms of amyloid beta (Abeta) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as transgenic mouse models of AD. Although the pathological significance of these shortened forms Abeta is not completely understood, previous studies have demonstrated that t...

In search of reducing vaccine production costs', a recombinant M13 phage version of the anti-cysticercosis tripeptide vaccine (S3Pvac) was developed. The efficacy of S3Pvac-Phage vs. placebo was evaluated in a randomized trial that included 1,047 rural pigs in 16 villages of Central Mexico. Three to five months after vaccination 530 pigs were exami...

Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer's disease. However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of targets have deleterious effects on cel...

Active and passive immunotherapy targeted at the amyloid-beta (Abeta) peptide has been proposed as therapeutic approach against Alzheimer's disease (AD), and efforts towards the generation and application of antibody-based reagents that are capable of preventing and clearing amyloid aggregates are currently under active investigation. Previously, w...

Vaccination of pigs may curtail Taenia solium transmission by reducing the number of cysticerci, the precursors of adult intestinal tapeworms in humans. Several antigen preparations induce protection against porcine cysticercosis in experimental settings but only one subunit vaccine (S3Pvac) has been tested and proved effective in the field against...

Taenia solium cysticercosis is a parasitic disease frequently affecting human health and the pig industry in many developing countries. A synthetic peptide vaccine (designated S3Pvac) against porcine cysticercosis has been developed previously as an aid to interrupt transmission and has been shown to be effective. The results of the present study s...

Extracellular and intraneuronal formation of amyloid-beta (Abeta) deposits have been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of Abeta neurotoxicity is not completely understood. Previous studies suggest that binding of Abeta with a number of targets have deleterious effects on cell...

A novel cDNA cloning strategy consisting in elimination of non-coding DNA sequences from 3' regions of cDNAs was applied to construct the Taenia crassiceps phage displayed cDNA expression library. After biopanning using immune sera, three phage clones expressing T. crassiceps-derived antigens specifically recognizing antibodies present in cerebrosp...

Cell-surface saccharides of Mycobacterium tuberculosis appear to be crucial factors in tuberculosis pathogenicity and could be useful antigens in tuberculosis immunodiagnosis. In the present study, we report the successful antigenic and immunogenic mimicry of mannose-containing cell-wall compounds of M. tuberculosis by dodecamer peptides identified...

In Alzheimer's disease (AD) beta-amyloid peptide accumulates in the brain in different forms including fibrils. Amyloid fibrils could be recognized as foreign by the mature immune system since they are not present during its development. Thus, using mouse antisera raised against the fibrillar form of Abeta42, we have screened two phage peptide libr...

A library of phage-displayed human single-chain Fv (scFv) antibodies was selected against the human amyloid-beta peptide (Abeta42). Two new anti-Abeta42 phage-displayed scFvs antibodies were obtained, and the sequences of their V(H) and Vkappa genes were analyzed. A synthetic peptide based on the sequence of Ig heavy chain (V(H)) complementarity-de...

The HIV-1 envelope glycoprotein gp41 contains Cys(X)5Cys motif, which has been shown to elicit a strong antibody response in almost all HIV-1 infected individuals. This disulfide-bonded loop region is conserved in most retroviruses suggesting the existence of an essential function in virus life cycle. In this study, we displayed the peptides compri...

A single-chain fragment variable (scFv) antibody library displayed on phage was constructed using spleen cells from mice immunized with human amyloid-beta peptide (Abeta42). This first anti-Abeta42 scFv immune antibody library was selected against human Abeta42. A number of positive clones were obtained, and sequences of VH and Vkappa genes were an...

The aim of this study was to test the capacity of recombinant phages to deliver antigens for vaccination against porcine cysticercosis. Thus, three peptides (KETc1, KETc12, GK1) and a recombinant antigen KETc7, previously proven to induce high levels of protection against pig cysticercosis, were expressed on the surface of the M13 bacteriophage at...

Antibody-dependent cellular cytotoxicity (ADCC) is a host defense mechanism in which Fc receptor-bearing effector cells in combination with antigen-specific antibodies recognize and kill antigen-expressing target cells. The authors previously described a murine monoclonal antibody (MAb-ID6) that mediated ADCC activity against HIV-infected cells. It...

Cysticercosis caused by Taenia solium frequently affects human health and rustic porciculture. Cysticerci may localize in the central nervous system of humans causing neurocysticercosis, a major health problem in undeveloped countries. Prevalence and intensity of this disease in pigs and humans are related to social factors (poor personal hygiene,...

Three random phage display peptide libraries were screened with sera from human papillomavirus (HPV)-infected patients to characterize the specificities of antibodies present in patients' sera and to identify molecules that correspond to or mimic natural epitopes; 141 phage clones were randomly selected in three rounds of bioselection and their bin...

Phage display is a powerful technology for selecting and engineering peptides and proteins expressed on the surface of filamentous bacteriophage. The advantages of phage display technology over other research tools and its' great potential have been demonstrated by successful application of phage display in diverse fields of biomedical/clinical res...

DNA immunization or inoculation is a recent vaccination method that induces both humoral and cellular immune responses in a range of hosts. Independent of the route or site of vaccination, the transfer of antigen-presenting cells (APC) or antigens into lymphoid organs is necessary. The aim of this investigation was to test whether intraspleen (i.s....

GPIIb/IIIa, the human platelet glycoprotein complex, is the autoantigen most commonly recognized by autoantibodies in autoimmune thrombocytopenic purpura (AITP). Two murine monoclonal antibodies (mAbs), namely Y2/51 and 5B12, directed against gpIIIa and gpIIb/IIIa, respectively, and rabbit anti-human platelet polyclonal antibodies have been used to...

cDNA expression library immunization (cDELI), based on the use of a large number of pathogen's cDNA clones, has been previously used in our laboratory in an experimental model of murine Taenia crassiceps cysticercosis. In this study we show that ex vivo immunization of mice with macrophages pulsed in vitro with plasmid DNA containing cDNA expressio...

A new type of immunogenic molecule was engineered by replacing all three complementarity-determining-region (CDR) loops of the human immunoglobulin (Ig) heavy-chain variable (V(H)) domain with the Taenia crassiceps epitope PT1 (PPPVDYLYQT) and by displaying this construct on the surfaces of M13 bacteriophage. When BALB/c mice were immunized with su...

The Taenia crassiceps recombinant antigen KETc7 has been shown to be effective as a vaccine against experimental murine cysticercosis, a laboratory model used to test potentially promising molecules against porcine Taenia solium cysticercosis. Based on the deduced amino acid sequence of this proline-rich polypeptide, three fragments, GK-1, GK-2, an...

To identify epitopes for antibodies present in cerebrospinal fluid (CSF) samples from two patients with confirmed neurocysticercosis, we used a phage peptide library that displayed random dodecapeptides as a fusion to the minor coat protein (pIII) of phage M13. To increase the specificity of selection, plates coated with anti-human Fc antibody were...

Genetic or DNA-based immunization, including genomic immunization, has shown to be a viable alternative approach to induce protective immunity against a number of pathogens in several disease models. Here we describe a new method, cDNA expression library immunization (cDELI), based on the use of a large number of cDNA clones. This immunization stra...

A random heptapeptide phage-displayed library was screened with two serum samples from autoimmune thrombocytopenic purpura (AITP) patients to address the repertoire of autoantigenic epitopes involved in platelet destruction. We obtained a panel of affinity-selected phage clones that have been shown to react in enzyme-linked immunosorbent assay with...

We describe the cloning and the evaluation of the protective capacity of 5 recombinant antigens expressed during the cysticercus stage of both Taenia crassiceps and Taenia solium. A cDNA library was constructed in bacteriophage lambda ZAP using mRNA isolated from larvae of T. crassiceps of the ORF strain. The recombinant phage library was screened...

The screening of a cDNA library of Taenia crassiceps revealed a clone designated KETc7 that induced high levels of protection against murine cysticercosis in previous experiments. The molecular structure of the deduced 100-amino acid sequence of the corresponding proline-rich polypeptide was studied to detect potentially immunologically active epit...

The development of vaccines against antigenically variable pathogens and diseases represents major scientific challenge. The list of such pathogens is large and includes AIDS, malaria, influenza, hepatitis and many forms of cancers. Despite seemingly different nature of these diseases and infections, they have clearly similar features regarding the...