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CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches. [ABSTRACT FROM AUTHOR]

Currently, one of the tasks facing breeders is the creation of new varieties in terms of their economically important characteristics, close to the developed models of the «ideal variety». The main purpose of the research is a comparative analysis of economically important indicators of a new AGU 75 variety of wintering oat of the dual direction, and the compliance with the parameters of the idiotype for further use as a genetic source. The basis for this approach was the study of the variety in the nursery of competitive variety testing in the period of 2000–2015. The studies were carried out in the soil and climatic conditions of the southern foothill zone of the North-Western Caucasus according to the generally accepted methods and agrotechnics of cultivation. As part of our research we used long-term experimental data from field observations and records, laboratory studies, and the biochemical composition of grain. The article gives an assessment of the duration of the growing season, winter hardiness, yield, resistance to lodging and major diseases (crown and stem rust, septoria, head smut) of the AGU 75 variety in relation to the idiotype. A comparative analysis of the elements of the crop structure (productive tillering, panicle length, number of spikelets, number of grains, grain weight per panicle, grain weight per plant, weight of 1000 grains) of varieties and models was carried out. The content of fat and protein, as well as the filminess of the grain of the analyzed variety and ideal type, were determined. Based on the comparative analysis of economically useful traits of AGU 75 variety, the degree of their compliance with the previously developed optimal parameters of the wintering oat model variant was revealed. The expediency of using AGU 75 variety as a source of valuable traits in breeding work to increase winter hardiness, productivity, resistance to lodging and diseases, early maturity, shattering, filminess, as well as elements of the crop structure – productive tillering, grain weight per plant was experimentally confirmed.

The ideal rice phenotype is that of plants exhibiting fewer panicles with high biomass, large grain number, flag leaf area with small insertion angles, and an erected morphology improving light interception. The sunflower transcription factor HaHB11, homeodomain–leucine zipper I, confers increased seed yield and abiotic stress tolerance to Arabidopsis and maize. Here, we report the obtaining and characterization of rice plants expressing HaHB11 driven by its promoter or the 35S constitutive one. Transgenic p35S:HaHB11 plants closely resembled the ideal high-yield phenotype, whereas those carrying the pHaHB11:HaHB11 construct were hard to distinguish from the wild type. The former had an erected architecture, enhanced vegetative leaf biomass, rolled flag leaves with a larger surface, sharper insertion angles insensitive to brassinosteroids, and higher harvest index and seed biomass than the wild type. The combination of the distinct features exhibited by p35S:HaHB11 plants, including the increased number of set grains per panicle, supports the high-yield phenotype. We wondered where HaHB11 has to be expressed to achieve the high-yield phenotype and evaluated HaHB11 expression levels in all tissues. The results indicate that its expression is particularly necessary in the flag leaf and panicle to produce the ideal phenotype. [ABSTRACT FROM AUTHOR]

1F7 is a monoclonal antibody that recognizes an idiotypic determinant expressed on primate antibodies binding to HIV-1 and hepatitis C proteins. This monoclonal antibody was used as a tool to dissect the immune response in humans infected with HIV-1 and hepatitis B. Furthermore, 1F7 was also used to manipulate the immune response against HIV-1 in macaques. The generation of a monoclonal antibody describing a network suggests similar antibodies could be developed as tools to dissect entangled networks in autoimmune diseases and allergic reactions. This review discusses the body of work done with 1F7 in the light of contemporary immunology. [ABSTRACT FROM AUTHOR]

Clinical anti-drug-antibody (ADA) responses represent a substantial obstacle to the development of efficacious therapeutic antibodies. The enhanced ADA production against the idiotype (Id) often displayed by cancer immunotherapy antibodies (CitAbs) can lead to exposure loss and subsequently affect anti-tumor efficacy and cause undesired effects on safety. Thus, ADA responses contribute to prolonged clinical development and high attrition rates. Most conventional therapeutic antibodies are now of human origin or humanized proteins, and are hence immunologically tolerized in most patients. In contrast, the contribution of additional factors, other than the protein sequence, to the higher rates of clinical ADA to certain CitAbs, remains poorly understood. Here, we used human immunoglobulin gamma 1 (IgG1) transgenic mice (named “hIgG1 transgenic mice” or “TG”), which are immunologically tolerant to human IgG1, to study the immunogenicity of 13 conventional antibodies and 2 CitAbs. We found that tolerance to non-germline encoded Ids is maintained in part by the function of neonatal Fc-receptor (FcRn). Additionally, the incorporation of T cell-engaging moieties like an interleukin 2 (IL-2)-based immunocytokine or a CD3ε-specific antigen-binding fragment (Fab) was sufficient to revert tolerance and trigger ADA production directed to the Id of these compounds. We postulate that T cell receptor or IL-2 receptor activation may result in activation of unresponsive T cells specific for the crystallizable fragment (Fc) that typically inactivate Id-specific B cells and mediate “linked-antigen tolerance”. Reversal of this unresponsiveness by the action of CitAbs on T cells may be the cause of undesired ADA responses.Abbreviations ADA Anti-Drug Antibodies; BCR B Cell Receptor; BId Idiotype-specific B Cell; BiTE Bispecific T cell Engager; BMC Bone Marrow Chimeric Mice; BSA Bovine Serum Albumin; CDR Complementary Determining Region; CEA Carcinoembryonic Antigen; CIT Cancer Immunotherapy; CitAbs Cancer Immunotherapy Antibodies; DC Dendritic Cell; ELISA Enzyme-Linked Immunosorbent Assay; FcRn Neonatal Fc Receptor; FcyR Fc gamma Receptor; GM-CSF Granulocyte-Macrophage Colony Stimulating Factor; gMFI Geometric Mean Fluorescence Intensity; H Heavy Chain; IC Immune Complex; Id Idiotype; IgA Immunoglobulin alpha; IgG1 Immunoglobulin gamma 1; IL-2 Interleukin 2; IL-2R Interleukin 2 Receptor; IL2v Interleukin 2 Variant; IVIG1 Intravenous Immunoglobulin 1; KLH Keyhole Limpet Hemocyanin; L Light Chain; MAPPs MHC-associated Peptide Proteomics; MHC Major Histocompatibility Complex; PBMC Peripheral Blood Mononuclear Cells; PBS Phosphate Buffered Saline; SHM Somatic Hypermutation; scFv Single-chain Variable Fragment; TCR T cell Receptor; TFc Fc-specific T cell; TId Id-specific T cell; UV Ultraviolet; V Variable.

Abstract The idiotype network is experimentally modified to provide protective immunity against various microbial pathogens. Both internal and non-internal image-idiotype antibodies can trigger specific immune responses to antigens. The current outbreak of Severe Acute Respiratory Syndrome 2 (SARS-2) has provided a great opportunity to take advantage of idiotype / anti-idiotype antibodies as a protective regimen when no approved vaccine is available on earth. The current review identifies successful applications of idiotype/ anti-idiotype antibodies in various viral diseases and highlights their importance in COVID-19 pandemics. In the absence of vaccines and targeted therapies, polyclonal idiotype/ anti-idiotype antibodies against the viral structure may be a potential approach to the prevention and treatment of COVID-19 patients.

The ideal rice phenotype is that of plants exhibiting fewer panicles with high biomass, large grain number, flag leaf area with small insertion angles, and an erected morphology improving light interception. The sunflower transcription factor HaHB11, homeodomain–leucine zipper I, confers increased seed yield and abiotic stress tolerance to Arabidopsis and maize. Here, we report the obtaining and characterization of rice plants expressing HaHB11 driven by its promoter or the 35S constitutive one. Transgenic p35S:HaHB11 plants closely resembled the ideal high-yield phenotype, whereas those carrying the pHaHB11:HaHB11 construct were hard to distinguish from the wild type. The former had an erected architecture, enhanced vegetative leaf biomass, rolled flag leaves with a larger surface, sharper insertion angles insensitive to brassinosteroids, and higher harvest index and seed biomass than the wild type. The combination of the distinct features exhibited by p35S:HaHB11 plants, including the increased number of set grains per panicle, supports the high-yield phenotype. We wondered where HaHB11 has to be expressed to achieve the high-yield phenotype and evaluated HaHB11 expression levels in all tissues. The results indicate that its expression is particularly necessary in the flag leaf and panicle to produce the ideal phenotype.

T cell-derived cancers are hallmarked by heterogeneity, aggressiveness, and poor clinical outcomes. Available targeted therapies are severely limited due to a lack of target antigens that allow discrimination of malignant from healthy T cells. Here, we report a novel approach for the treatment of T cell diseases based on targeting the clonally rearranged T cell receptor displayed by the cancerous T cell population. As a proof of concept, we identified an antibody with unique specificity toward a distinct T cell receptor (TCR) and developed antibody-drug conjugates, precisely recognizing and eliminating target T cells while preserving overall T cell repertoire integrity and cellular immunity. Our anti-TCR antibody-drug conjugates demonstrated effective receptor-mediated cell internalization, associated with induction of cancer cell death with strong signs of apoptosis. Furthermore, cell proliferation-inhibiting bystander effects observed on target-negative cells may contribute to the molecules' anti-tumor properties precluding potential tumor escape mechanisms. To our knowledge, this represents the first anti-TCR antibody-drug conjugate designed as custom-tailored immunotherapy for T cell-driven pathologies., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The B-cell receptor (BCR) is a key player of the adaptive immune system. It is a unique part of immunoglobulin (Ig) molecules expressed on the surface of B cells. In case of many B-cell lymphomas, the tumor cells express a tumor-specific and functionally active BCR, also known as idiotype. Utilizing the idiotype as target for lymphoma therapy has emerged to be demanding since the idiotype differs from patient to patient. Previous studies have shown that shark-derived antibody domains (vNARs) isolated from a semi-synthetic CDR3-randomized library allow for the rapid generation of anti-idiotype binders. In this study, we evaluated the potential of generating patient-specific binders against the idiotype of lymphomas. To this end, the BCRs of three different lymphoma cell lines SUP-B8, Daudi, and IM-9 were identified, the variable domains were reformatted and the resulting monoclonal antibodies produced. The SUP-B8 BCR served as antigen in fluorescence-activated cell sorting (FACS)-based screening of the yeast-displayed vNAR libraries which resulted after three rounds of screening in the enrichment of antigen-binding vNARs. Five vNARs were expressed as Fc fusion proteins and consequently analyzed for their binding to soluble antigen using biolayer interferometry (BLI) revealing binding constants in the lower single-digit nanomolar range. These variants showed specific binding to the parental SUP-B8 cell line confirming a similar folding of the recombinantly expressed proteins compared with the native cell surface-presented BCR. First initial experiments to utilize the generated vNAR-Fc variants for BCR-clustering to induce apoptosis or ADCC/ADCP did not result in a significant decrease of cell viability. Here, we report an alternative approach for a personalized B-cell lymphoma therapy based on the construction of vNAR-Fc antibody-drug conjugates to enable specific killing of malignant B cells, which may widen the therapeutic window for B-cell lymphoma therapy.

Abstract Background There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a “watchful waiting” approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial. Methods These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow. Discussion This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches. Trial registration ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010.

The B-cell receptor (BCR) is a key player of the adaptive immune system. It is a unique part of immunoglobulin (Ig) molecules expressed on the surface of B cells. In case of many B-cell lymphomas, the tumor cells express a tumor-specific and functionally active BCR, also known as idiotype. Utilizing the idiotype as target for lymphoma therapy has emerged to be demanding since the idiotype differs from patient to patient. Previous studies have shown that shark-derived antibody domains (vNARs) isolated from a semi-synthetic CDR3-randomized library allow for the rapid generation of anti-idiotype binders. In this study, we evaluated the potential of generating patient-specific binders against the idiotype of lymphomas. To this end, the BCRs of three different lymphoma cell lines SUP-B8, Daudi, and IM-9 were identified, the variable domains were reformatted and the resulting monoclonal antibodies produced. The SUP-B8 BCR served as antigen in fluorescence-activated cell sorting (FACS)-based screening of the yeast-displayed vNAR libraries which resulted after three rounds of screening in the enrichment of antigen-binding vNARs. Five vNARs were expressed as Fc fusion proteins and consequently analyzed for their binding to soluble antigen using biolayer interferometry (BLI) revealing binding constants in the lower single-digit nanomolar range. These variants showed specific binding to the parental SUP-B8 cell line confirming a similar folding of the recombinantly expressed proteins compared with the native cell surface-presented BCR. First initial experiments to utilize the generated vNAR-Fc variants for BCR-clustering to induce apoptosis or ADCC/ADCP did not result in a significant decrease of cell viability. Here, we report an alternative approach for a personalized B-cell lymphoma therapy based on the construction of vNAR-Fc antibody-drug conjugates to enable specific killing of malignant B cells, which may widen the therapeutic window for B-cell lymphoma therapy. [ABSTRACT FROM AUTHOR]

We report on the design of a phase I, non-randomized, open-label study of idiotypic DNA vaccination in patients with B-cell non-Hodgkin's lymphoma (ISRCTN31090206). The study uses DNA fusion gene vaccination encoding patient-specific single chain variable fragment, or idiotype, linked to an immunostimulatory sequence. Two types of immunostimulatory sequence are being explored: potato virus X coat protein and human chemokine MIP3α. Linear polyethylenimine with low molecular weight (8 kDa) is used as a synthetic vehicle for vaccine delivery. Humoral and T-cellular immune responses to vaccination will be measured by ELISA and ELISPOT, respectively. The primary study endpoints are safety, tolerability and immunogenicity of DNA-PEI vaccination.

The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for immunotherapy. Here, the idiotype network theory is revisited with regard to the development of efficacious anti-idiotype vaccines. The experience of polyclonal anti-Idiotype reagents in animal models as well as an understanding of the immune response in humans lends to the proposition that polyclonal anti-Idiotype vaccines will be more effective compared to monoclonal-based anti-Idiotype vaccines. This novel strategy can be adapted in Biotech-standard production of therapeutic antibodies.

Antigen determinants (epitopes) are recognized by the combining sites (paratopes) of B and T cell antigen receptors (BCR/TCR), which again express clone-specific epitopes (idiotopes) that can be recognized by BCR/TCR not only of genetically different donors but also within the autologous immune system. While xenogeneic and allogeneic anti-idiotypic BCR/TCR are broadly cross-reactive, only autologous anti-idiotypes are truly specific and of functional regulatory relevance within a particular immune system. Autologous BCR/TCR idiotopes are (a) somatically created at the third complementarity-determining regions, (b) through mutations introduced into BCRs during adaptive immune responses, and (c) through the conformational impact of both. As these idiotypic characters have no genomic counterparts they have to be regarded as antigen receptor-intrinsic nonself-portions. Although foreign, however, they are per se non-immunogenic, but in conjunction with immunogenicity- and adjuvanticity-providing antigen-induced immune responses, they induce abating regulatory idiotypic chain reactions. The dualistic nature of antigen receptors of seeing antigens (self and nonself alike) and being nonself at the same time has far reaching consequences for an understanding of the regulation of adaptive immune responses.

Antigen determinants (epitopes) are recognized by the combining sites (paratopes) of B and T cell antigen receptors (BCR/TCR), which again express clone-specific epitopes (idiotopes) that can be recognized by BCR/TCR not only of genetically different donors but also within the autologous immune system. While xenogeneic and allogeneic anti-idiotypic BCR/TCR are broadly cross-reactive, only autologous anti-idiotypes are truly specific and of functional regulatory relevance within a particular immune system. Autologous BCR/TCR idiotopes are (a) somatically created at the third complementarity-determining regions, (b) through mutations introduced into BCRs during adaptive immune responses, and (c) through the conformational impact of both. As these idiotypic characters have no genomic counterparts they have to be regarded as antigen receptor-intrinsic nonself-portions. Although foreign, however, they are per se non-immunogenic, but in conjunction with immunogenicity- and adjuvanticity-providing antigen-induced immune responses, they induce abating regulatory idiotypic chain reactions. The dualistic nature of antigen receptors of seeing antigens (self and nonself alike) and being nonself at the same time has far reaching consequences for an understanding of the regulation of adaptive immune responses. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) have come to dominate the biologics market in human cancer therapy. Nevertheless, in veterinary medicine, very few clinical trials have been initiated using this form of therapy. Some of the advantages of mAb therapeutics over conventional drugs are high specificity, precise mode of action and long half-life, which favour infrequent dosing of the antibody. Further advancement in the field of biomedical sciences has led to the production of different forms of antibodies, such as single chain antibody fragment, Fab, bi-specific antibodies and drug conjugates for use in diagnostic and therapeutic purposes. This review describes the potential for mAbs in veterinary oncology in supporting both diagnosis and therapy of cancer. The technical and financial hurdles to facilitate clinical acceptance of mAbs are explored and insights into novel technologies and targets that could support more rapid clinical development are offered. [ABSTRACT FROM AUTHOR]

Keywords: antibody; idiotype; selection; natural antibody; therapeutic antibody He suggested that antibodies could be recognized as foreign, inducing other antibodies and thereby forming a network. 18 Hedrick, SM, Cohen, DI, Nielsen, EA, Davis, MM, Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Antibody, idiotype, selection, natural antibody, therapeutic antibody. [Extracted from the article]

The homophilic potential emerges as an important biological principle to boost the potency of immunoglobulins. Since homophilic antibodies in human and mouse sera exist prior environmental exposure they are part of the natural antibody repertoire. Nevertheless, hemophilic properties are also identified in induced antibody repertoire. The use of homophilicity of antibodies in the adaptive immunity signifies an archetypic antibody structure. The unique feature of homophilicity in the antibody repertoire also highlights an important mechanism to boost the antibody potency to protect against infection and atherosclerosis as well to treat cancer patients.

In this review, we trace the concept and potential functional role of regulatory idiotypes in the immune response to human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, and hepatitis C virus (HCV). A major idiotype involved in these viral infections is recognized and defined by a murine monoclonal antibody (1F7). Antibodies expressing the idiotype defined by 1F7 are dominant in HIV-1 infection and are also found on many broadly neutralizing antibodies against HIV-1. This regulatory idiotypic axis offers opportunities for exploitation in vaccine development for HIV-1, HCV and other chronic viral infections.

Hybridoma-derived idiotype vaccines have been used for the experimental treatment of human lymphoma over the last twenty years, providing evidence of biological efficacy, clinical efficacy and clinical benefit. However, the product that has come closer to regulatory approval is unlikely to clear that hurdle due to the insufficiently robust data obtained in a recently closed clinical trial. This review aims at discussing the reasons for hybridoma-derived idiotype vaccines, more difficult to produce but also more successful than recombinant idiotype vaccines so far, are unlikely to gain regulatory approval. In particular, it is necessary to examine the many peculiar features of this therapeutic approach in a broader context, with special attention to concepts like customized active immunotherapy and randomization. Most published trials based on hybridoma-derived idiotype vaccines are being analyzed, together with the yet non-peer reviewed data from the only randomized study conducted so far with this product, and with the main trials on recombinant idiotype vaccines for thorough comparison. All in all, the sole randomized trial ever conducted on hybridoma-derived idiotype vaccines failed to achieve its primary clinical end point because of an insufficient accrual and because the statistical significance achieved was not as stringent as required for regulatory approval.

B-cell lymphomas express a functionally active and truly tumor-specific cell-surface product, the variable region of the B-cell receptor (BCR), otherwise known as idiotype. The tumor idiotype differs, however, from patient to patient, making it a technical challenge to exploit for therapy. We have developed a method of targeting idiotype by using a semisynthetic personalized therapeutic that is more practical to produce on a patient-by-patient basis than monoclonal antibodies. In this method, a small peptide with affinity for a tumor idiotype is identified by screening a library, chemically synthesized, and then affixed to the amino terminus of a premade IgG Fc protein. We demonstrate that the resultant semisynthetic anti-idiotype peptibodies kill tumor cells in vitro with specificity, trigger tumor cell phagocytosis by macrophages, and efficiently clear human lymphoma in a murine xenograft model. This method could be used to target tumor with true precision on a personalized basis. [ABSTRACT FROM AUTHOR]

Tumors require blood supply and, to overcome this restriction, induce angiogenesis. Vascular endothelial growth factor ( VEGF) plays an important role in this process, which explains the great number of antiangiogenic therapies targeting VEGF. The research and development of targeted therapy has led to the approval of bevacizumab, a humanized anti- VEGF monoclonal antibody ( mAb), in clinical settings. However, side effects have been reported, usually as a consequence of bolus-dose administration of the antibody. This limitation could be circumvented through the use of anti-idiotype (Id) antibodies. In the present study, we evaluated the efficacy of an active VEGF-binding immune response generated by an anti-bevacizumab idiotype mAb, 10.D7. The 10.D7 anti-Id mAb vaccination led to detectable levels of VEGF-binding anti-anti-Id antibodies. In order to examine whether this humoral immune response could have implications for tumor development, 10.D7-immunized mice were challenged with B16-F10 tumor cells. Mice immunized with 10.D7 anti-Id mAb revealed reduced tumor growth when compared to control groups. Histological analyses of tumor sections from 10.D7-immunized mice showed increased necrotic areas, decreased CD31-positive vascular density and reduced CD68-positive cell infiltration. Our results encourage further therapeutic studies, particularly if one considers that the anti-Id therapeutic vaccination maintains stable levels of VEGF-binding antibodies, which might be useful in the control of tumor relapse. [ABSTRACT FROM AUTHOR]

The homophilic potential emerges as an important biological principle to boost the potency of immunoglobulins. Since homophilic antibodies in human and mouse sera exist prior environmental exposure, they are part of the natural antibody repertoire. Nevertheless, hemophilic properties are also identified in induced antibody repertoire. The use of homophilicity of antibodies in the adaptive immunity signifies an archetypic antibody structure. The unique feature of homophilicity in the antibody repertoire also highlights an important mechanism to boost the antibody potency to protect against infection and atherosclerosis as well to treat cancer patients. [ABSTRACT FROM AUTHOR]

In this review, we trace the concept and potential functional role of regulatory idiotypes in the immune response to human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, and hepatitis C virus (HCV). A major idiotype involved in these viral infections is recognized and defined by a murine monoclonal antibody (1F7). Antibodies expressing the idiotype defined by 1F7 are dominant in HIV-1 infection and are also found on many broadly neutralizing antibodies against HIV-1. This regulatory idiotypic axis offers opportunities for exploitation in vaccine development for HIV-1, HCV, and other chronic viral infections. [ABSTRACT FROM AUTHOR]

We report on the safety and immunogenicity of idiotypic DNA vaccination in a phase I, non-randomised, open-label study in patients with multiple myeloma. The study used DNA fusion gene vaccines encoding patient-specific single chain variable fragment, or idiotype (Id), linked to fragment C (FrC) of tetanus toxin. Patients in complete or partial response following high-dose chemotherapy and autologous stem cell transplant were vaccinated intramuscularly with 1 mg DNA on six occasions, beginning at least 6 months post-transplant; follow-up was to week 52. Fourteen patients were enrolled on study and completed vaccinations. Idiotypic DNA vaccines were well tolerated with vaccine-related adverse events limited to low-grade constitutional symptoms. FrC- and Id-specific T-cell responses were detected by ex vivo ELISPOT in 9/14 and 3/14 patients, respectively. A boost of pre-existing anti-FrC antibody (Ab) was detected by ELISA in 8/14 patients, whilst anti-Id Ab was generated in 1/13 patients. Overall, four patients (29 %) made an immune response to FrC and Id, with six patients (43 %) responding to FrC alone. Over the 52-week study period, serum paraprotein was undetectable, decreased or remained stable for ten patients (71 %), whilst ongoing CR/PR was maintained for 11 patients (79 %). The median time to progression was 38.0 months for 13/14 patients. Overall survival was 64 % after a median follow-up of 85.6 months. [ABSTRACT FROM AUTHOR]

Idiotype (Id)-based immunotherapy has been exploited as cancer treatment option. Conceived as therapy for malignancies bearing idiotypic antigens, it has been also extended to solid tumours because of the capacity of anti-idiotypic antibodies to mimick Id-unrelated antigens. In both these two settings, efforts are being made to overcome the poor immune responsiveness often experienced when using self immunoglobulins as immunogens. Despite bearing a unique gene combination, and thus particular epitopes, it is normally difficult to stimulate the immune response against antibody variable regions. Different strategies are currently used to strengthen Id immunogenicity, such as concomitant use of immune-stimulating molecules, design of Id-containing immunogenic recombinant proteins, specific targeting of relevant immune cells and genetic immunization. This review focuses on the role of anti-Id vaccination in cancer management and on the current developments used to foster anti-idiotypic B- and T-cell responses.

Background: Idiotopes (Id) are antigenic determinants localized in variable (V) regions of Ig. Id-specific T and B cells (antibodies) play a role in immunotherapy of Id+ tumors. However, vaccine strategies that enhance Id-specific responses are needed. Methods: Id+ single chain Fragment variable (scFv) from multiple myelomas and B cell lymphomas were prepared in a fusion format that bivalently target surface molecules on antigen presenting cells (APC). APC-specific targeting units were either scFv from APC-specific mAb (anti-MHCII, anti-CD40) or chemokines (MIP-1α, RANTES). Homodimeric Id-vaccines were injected intramuscularly or intradermally as plasmids in mice, combined with electroporation. Results: (i) Transfected cells secreted plasmid-encoded Id+ fusion proteins to extracellular fluid followed by binding of vaccine molecules to APC. (ii) Targeted vaccine molecules increased Id-specific B and T cell responses. (iii) Bivalency and xenogeneic sequences both contributed to enhanced responses. (iv) Targeted Id DNA vaccines induced tumor resistance against challenges with Id+ tumors. (v) Human MIP-1α targeting units enhanced Id-specific responses in mice, due to a cross reaction with murine chemokine receptors. Thus, targeted vaccines designed for humans can be quality tested in mice. (vi) Human Id+ scFv from 4 multiple myeloma patients were inserted into the vaccine format and were successfully tested in mice. (vii) Human MIP-1α vaccine proteins enhanced human T cell responses in vitro (viii) A hypothetical model for how the APC-targeted vaccine molecules enhance Id-specific T and B cells is presented. Conclusions: Targeted DNA Id-vaccines show promising results in preclinical studies, paving the way for testing in patients.