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The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

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Resumen El mieloma múltiple (MM) sigue siendo una patología incurable a pesar de las mejoras en las opciones de tratamiento que se desarrollaron en los últimos años. El antígeno de maduración de células B (BCMA) se expresa predominantemente en células de linaje B y representa un nuevo objetivo terapéutico prometedor para el MM recaído refractario (MMRR). Teclistamab (TECVAYLI) es el primer anticuerpo biespecífico de redirección de células T (CD3) contra BCMA (Figura 1) aprobado por la Administración de Drogas y Alimentos de Estados Unidos (FDA) en 2022 para pacientes con MMRR a 3 líneas de tratamiento previos, incluyendo Inhibi-dores de Proteosoma (IP), Inmunomoduladores (IMIDS), Anticuerpos Monoclonales (AcMo). La neurotoxicidad asociada a células efectoras inmunitarias (ICANS), el síndrome de liberación de citoquinas (CRS) e infecciones por hipogamaglobulinemia son los efectos adversos más comunes.

Abstract Multiple myeloma (MM) remains an incurable disease despite improvements in treatment options that have been developed recent years. B cell maturation antigen (BCMA) is predominantly expressed on B lineage cells and represents a promising new therapeutic target for relapsed re-fractory MM (RRMM). Teclistamab (TECVAYLI) is the first bispecific T cell (CD3) redirecting antibody against BCMA (Figure 1) approved by the US Food and Drug Administration (FDA) in 2022 for patients with RRMM on 3 prior lines of treatment, including Proteasome Inhibitors (PI), Immunomodulators (IMIDS), Monoclonal Antibodies (mAb). ICANS (immune effector cell-associated neurotoxicity), CRS (cytokine release syndrome), and hypogammaglobulinemia infections are the most common adverse effects.

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In recent years, cancer has become one of the primary causes of mortality, approximately 10 million deaths worldwide each year. The most advanced, chimeric antigen receptor (CAR) T cell immunotherapy has turned out as a promising treatment for cancer. CAR-T cell therapy involves the genetic modification of T cells obtained from the patient's blood, and infusion back to the patients. CAR-T cell immunotherapy has led to a significant improvement in the remission rates of hematological cancers. CAR-T cell therapy presently limited to hematological cancers, there are ongoing efforts to develop additional CAR constructs such as bispecific CAR, tandem CAR, inhibitory CAR, combined antigens, CRISPR gene-editing, and nanoparticle delivery. With these advancements, CAR-T cell therapy holds promise concerning potential to improve upon traditional cancer treatments such as chemotherapy and radiation while reducing associated toxicities. This review covers recent advances and advantages of CAR-T cell immunotherapy.

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Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy can provide durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after failure of chemoimmunotherapy. However, patients who are refractory or relapsing after CAR-T therapy have poor outcomes. Multiple mechanisms of CAR-T therapy failure have been proposed but management of these patients remains a challenge. As CAR-T therapy moves earlier in the treatment of DLBCL, we urgently need trials focused on patients with relapse after CAR-T therapy. Recent advances in novel immunotherapies such as bispecific antibodies, antibody-drug conjugates and next-generation CAR-T therapies may provide avenues for treatment. Here we review the available data on using these drugs after failure of CAR-T therapy and provide a framework for the ideal sequencing of these novel agents.

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INTRODUCTION: Despite the use of multimodality therapy, locally advanced rectal cancer (LARC) still presents high rates of disease recurrence. Fluoropyrimidine-based chemotherapy concurrently with radiation therapy (RT) remains the cornerstone of neoadjuvant therapy of LARC, and novel therapies are urgently needed in order to improve the clinical outcomes. AREAS COVERED: We aim to summarize data from completed and ongoing clinical trials addressing the role of biological therapies, including monoclonal antibodies, immune checkpoint inhibitors (ICIs), antibody-drug conjugates, bispecific antibodies, and gene therapies in the systemic therapy of rectal cancer. EXPERT OPINION: Deeper understanding of the molecular biology of colorectal cancer (CRC) has allowed meaningful advances in the systemic therapy of metastatic disease in the past few years. The larger applicability of biological therapy in CRC, including genome-guided targeted therapy, antiangiogenics, and immunotherapy, gives us optimism for the personalized management of rectal cancer. Microsatellite instability (MSI) tumors have demonstrated high sensitivity to ICIs, and preliminary findings in the neoadjuvant setting of rectal cancer are promising. To date, antiangiogenic and anti-EGFR therapies in LARC have not demonstrated the same benefit seen in metastatic disease. The outstanding results accomplished by biomarker-guided therapy in metastatic CRC will guide future developments of biological therapy in LARC.

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Immunotherapy has redefined the treatment of cancer patients and it is constantly generating new advances and approaches. Among the multiple options of immunotherapy, bispecific antibodies (bsAbs) represent a novel thoughtful approach. These drugs integrate the action of the immune system in a strategy to redirect the activation of innate and adaptive immunity toward specific antigens and specific tumor locations. Here we discussed some basic aspects of the design and function of bsAbs, their main challenges and the state-of-the-art of these molecules in the treatment of hematological and solid malignancies and future perspectives.

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Abstract Background: Different immune mechanisms of myocardial damage involved in the pathophysiology of Chagas disease coexist with high titers of autoantibodies induced by T. cruzi . There are few studies in the literature about the adaptive role of anti-β1 and anti-M2 antibodies in chronic Chagas cardiomyopathy (CCC). Objectives: To evaluate the association between anti-β1 and anti-M2 antibodies with heart rate variability (HRV) parameters on 24h Holter monitoring and the rate-pressure product (RPP) on cardiopulmonary exercise testing (CPET). Methods: Anti-β1 and anti-M2 antibody titers were measured by enzyme-linked immunosorbent assay (ELISA) in 64 patients affected by CCC. Analysis of HRV was performed through the time-domain indices NNs, mean NN, SDNN, SDANN, SDNN index, NNNs, RMSSD, and pNN50. Spearman's correlation coefficient was used to assess the association between antibody titers and numerical variables. The Mann-Whitney test was used for comparison between two groups. Multiple linear regression was used to identify independent variables capable of explaining anti-β1 and anti-M2 antibody titers at the 5% significance level. Results: On 24h Holter, during the period of greatest parasympathetic activation (2:00-6:00 a.m.), an inverse association was found between anti-β1 titers and SDNN (rs=-0.13, p =0.041, n=43), as well as a direct association between anti-M2 titers and SDANN ( r s=0.317, p =0.039, n=43). Regarding CPET variables, anti-β1 titers were directly associated with RPP (rs=0.371, p =0.005, n=56). The subgroup of patients with a normal chronotropic response showed higher anti-β1 titers than the subgroup with an impaired response (p=0.023). RPP was an independent explanatory variable for anti-β1 titers, although with a low coefficient of determination (R2=0.147). Conclusion: The findings of this study suggest that, in patients with CCC, anti-β1 and anti-M2 antibodies may affect HRV parameters. RPP was directly associated with higher anti-β1 titers.

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Background: The diphtheria toxoid antigen is a major component in pediatric and booster combination vaccines and is known to raise a protective humoral immune response upon vaccination. Although antibodies are considered critical for diphtheria protection, little is known about the antigenic determinants that maintain humoral immunity. Methods: One-hundred and twelve 15 mer peptides covering the entire sequence of diphtheria toxin (DTx) protein were prepared by SPOT synthesis. The immunoreactivity of membrane-bound peptides with sera from mice immunized with a triple DTP vaccine allowed mapping of continuous B-cell epitopes, topological studies, multiantigen peptide (MAP) synthesis, and Enzyme-Linked Immunosorbent Assay (ELISA) development. Results: Twenty epitopes were identified, with two being in the signal peptide, five in the catalytic domain (CD), seven in the HBFT domain, and five in the receptor-binding domain (RBD). Two 17 mer (CB/Tx-2/12 and CB/DTx-4-13) derived biepitope peptides linked by a Gly-Gly spacer were chemically synthesized. The peptides were used as antigens to coat ELISA plates and assayed with human (huVS) and mice vaccinated sera (miVS) for in vitro diagnosis of diphtheria. The assay proved to be highly sensitive (99.96%) and specific (100%) for huVS and miVS and, when compared with a commercial ELISA test, demonstrated a high performance. Conclusions: Our work displayed the complete picture of the linear B cell IgG response epitope of the DTx responsible for the protective effect and demonstrated sufficient specificity and eligibility for phase IIB studies of some epitopes to develop new and fast diagnostic assays.

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INTRODUCTION: PD-L1 and PD-1 are two immune checkpoints and their presence in various types of tumors is related to a poor prognosis; this makes them highly relevant targets in the development of new therapies. Patent US2019010232 describes bispecific anti-PD-L1/PD-1 antibodies made with Azymetric technology. AREAS COVERED: Three bispecific antibodies that target PD-L1/PD-1 are described in US2019010232 patent and are proposed to play a relevant role in the treatment of cancer. EXPERT OPINION: Three bispecific antibodies that target PD-L1/PD-1 in US2019010232 demonstrated anti-tumor activity in lung cancer. However, no evidence is shown of the action of the antibodies against other cancers. An advantage of the bispecific antibodies of US2019010232 over combinatorial therapy is a greater decrease in tumor volume.

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INTRODUCTION: Due to the primary role of PD-1 and LAG-3 in regulating the immune response in tumors, there is a need to develop therapies focused on the inhibition of PD-1 and LAG-3 in order to improve the immune response in patients with cancer. The authors of US2018326054 patent propose a method to eradicate cancer by using bispecific anti-PD-1/LAG-3 antibodies. AREAS COVERED: The US2018326054 patent describes anti-PD-1/LAG3 antibodies, pharmaceutical composition that contains it, and their application for cancer treatment, particularly pancreatic carcinoma. Proof concept and preclinical results show anti-PD-1/LAG-3 bispecific antibodies bind and are internalized by CD4 + T cells thereby increasing their effector functions (release of Granzyme B and INF-γ) in the presence of tumor cells, and completely suppress tumors in a murine model. EXPERT OPINION: Anti-PD-1/LAG-3 bispecific antibodies of the US2018326054 patent are new in a general concept, but treatment data is only shown for pancreatic carcinoma. The results to be obtained in future clinical trials of safety and efficacy could conclude whether these bispecific anti-PD-1/LAG-3 antibodies will be useful in a cancer treatment scheme.

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Introduction: TIM3 and PD-1 are checkpoint inhibitors in cancer that coordinate the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of TIM3 and PD-1 and consequently improving the immune response in the various types of cancer. The authors of patent EP3356411A1 propose several anti-TIM3/anti-PD-1 bispecific antibodies, as well as the method for producing them and their pharmacological application in the treatment of cancer. Areas covered: Patent EP3356411A1 describes a method by producing anti-TIM3/anti-PD-1 bispecific antibodies and their potential in cancer treatment. Expert opinion: Data supporting the patent demonstrate the ability by producing anti-TIM3/anti-PD-1 bispecific antibodies. Although the proposed methodology is very interesting and promising, further studies are necessary to assess the clinical applicability of the inventions on cancer.

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PURPOSE OF REVIEW: The purpose of this review is to discuss the current recommendations for the use of bispecific antibodies (bsAb) in hematologic malignancies and explore the future in this field. RECENT FINDINGS: Bispecific antibodies are molecules able to target two different antigen-binding sites: one towards a tumor antigen and another to activate a cytotoxic cell. Phase II/III trials on blinatumomab for acute lymphoblastic leukemia (ALL) have demonstrated its efficacy for treating minimal residual disease (MRD+) and relapsed refractory (r/r) Philadelphia positive (Ph+) and negative (Ph-) ALL in adults and children. Currently, the only bispecific antibody (bsAb) approved for its use in hematologic malignancies is blinatumomab. However, multiple trials are under development not only to explore blinatumomab's clinical activity in other neoplasia, such as lymphoma or multiple myeloma, but also to develop new molecules against different antigens.

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