Understanding the Preclinical Efficacy of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) represent a therapeutic modality that guides chemotherapies to tumoral cells by using antibodies against tumor-associated antigens (TAAs). The antibody and the chemotherapy or payload are attached by a chemical structure called the linker. The strategy for the development of this type of drug was based on several rational pillars, including the use of a very potent payload and the use of specific antibodies acting only on antigens expressed on tumoral cells.

Present Scenario and Future Landscape of Payloads for ADCs: Focus on DNA-Interacting Agents.

ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index.

Overcoming limitations for antibody-based therapies targeting γδ T (Vg9Vd2) cells.

Therapeutic strategies targeting non-adaptive immune cells are currently in clinical development. γδT cells are a small subtype of T cells (1-10% of total T cells) that mediate their effector function without the necessity of the antigen presenting machinery, and also share functional properties with innate cells. Among the different γδT subtypes, antibodies against Vγ9Vδ2T have reported signs of clinical efficacy in early clinical studies.

Fluorescence lifetime nanothermometer based on the equilibrium formation of anthracene AIE-excimers in living cells.

The effective measurement of temperature in living systems at the nano and microscopic scales continues to be a challenge to this day. Here, we study the use of 2-(anthracen-2-yl)-1,3-diisopropylguanidine, 1, as a nanothermometer based on fluorescence lifetime measurements and its bioimaging applications. In aqueous solution, 1 is shown in aggregated form and the equilibrium between the two main aggregate types (T-shaped and π-π) is highly sensitive to the temperature.

Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.

The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D () gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage.

T-reg transcriptomic signatures identify response to check-point inhibitors.

Regulatory T cells (Tregs) is a subtype of CD4+ T cells that produce an inhibitory action against effector cells. In the present work we interrogated genomic datasets to explore the transcriptomic profile of breast tumors with high expression of Tregs. Only 0.

In Silico Transcriptomic Expression of MSR1 in Solid Tumors Is Associated with Responses to Anti-PD1 and Anti-CTLA4 Therapies.

Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration.

Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2.

The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2.

Exploring gastric cancer genetics: A turning point in common variable immunodeficiency.

Background: Gastric cancer (GC) stands as a prominent cause of cancer-related mortality and ranks second among the most frequently diagnosed malignancies in individuals with common variable immunodeficiency (CVID).

Objective: We sought to conduct a comprehensive, large-scale genetic analysis to explore the CVID-associated germline variant landscape within gastric adenocarcinoma samples and to seek to delineate the transcriptomic similarities between GC and CVID.

Methods: We investigated the presence of CVID-associated germline variants in 1591 GC samples and assessed their impact on tumor mutational load.

Evaluation of heteroscorpionate ligands as scaffolds for the generation of Ruthenium(II) metallodrugs in breast cancer therapy.

The modular synthesis of the heteroscorpionate core is explored as a tool for the rapid development of ruthenium-based therapeutic agents. Starting with a series of structurally diverse alcohol-NN ligands, a family of heteroscorpionate-based ruthenium derivatives was synthesized, characterized, and evaluated as an alternative to platinum therapy for breast cancer therapy. In vitro, the antitumoral activity of the novel derivatives was assessed in a series of breast cancer cell lines using UNICAM-1 and cisplatin as metallodrug control.

Considerations for the design of antibody drug conjugates (ADCs) for clinical development: lessons learned.

Antibody-drug conjugates (ADCs) have emerged as a novel therapeutic strategy that has successfully reached patient treatment in different clinical scenarios. ADCs are formed by an antibody against a specific tumor-associated antigen (TAA), a cytotoxic payload, and a chemical linker that binds both. To this regard, most efforts have been focused on target identification, antibody design and linker optimization, but other relevant aspects for clinical development have not received the necessary attention.

Uncovering therapeutic opportunities in the clinical development of antibody-drug conjugates.

Introduction: Antibody-drug conjugates (ADCs) are a family of therapeutic agents that have demonstrated clinical activity in several indications.

Material And Methods: In this article, we performed a deep analysis of their clinical landscape matched with public genomic human datasets from tumour antigen targets (TATs), to identify empty areas for clinical development.

Results: We observed that TATs used in haematological malignancies were more specific than the ones developed in solid cancers.

Formation of Highly Emissive Anthracene Excimers for Aggregation-Induced Emission/Self-Assembly Directed (Bio)imaging.

AIEgens have emerged as a promising alternative to molecular rotors in bioimaging applications. However, transferring the concept of aggregation-induced emission (AIE) from solution to living systems remains a challenge. Given the highly heterogeneous nature and the compartmentalization of the cell, different approaches are needed to control the self-assembly within the crowded intricate cellular environment.

Considerations for the clinical development of immuno-oncology agents in cancer.

Targeting of the immune system has shown to be a successful therapeutic approach in cancer, with the development of check point inhibitors (ICI) or T-cell engagers (TCE). As immuno-oncology agents modulate the immune system to attack cancer cells and do not act directly on oncogenic vulnerabilities, specific characteristics of these compounds should be taken in consideration during clinical development. In this review we will discuss relevant concepts including limitations of preclinical models, special pharmacologic boundaries, clinical development strategies such as the selection of clinical indication, line of treatment and backbone partner, as well as the endpoints and expected magnitude of benefit required at different stages of the drug development.

Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors.

Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity.

Genomic Mapping of Epidermal Growth Factor Receptor and Mesenchymal-Epithelial Transition-Up-Regulated Tumors Identifies Novel Therapeutic Opportunities.

Background: The identification of proteins in the cellular membrane of the tumoral cell is a key to the design of therapeutic agents. Recently, the bi-specific antibody amivantamab, targeting the oncogenic membrane proteins EGFR and MET, received regulatory approval for the treatment of adult patients with locally advanced or metastatic NSCLC.

Methods: The authors interrogated several publicly available genomic datasets to evaluate the expression of both receptors and PD-L1 in most of the solid and hematologic malignancies and focused on prostate adenocarcinoma (PRAD) and pancreatic adenocarcinoma (PAAD).

Macrophage Cell Membrane Coating on Piperine-Loaded MIL-100(Fe) Nanoparticles for Breast Cancer Treatment.

Piperine (PIP), a compound found in , has shown promise as a potential chemotherapeutic agent for breast cancer. However, its inherent toxicity has limited its application. To overcome this challenge, researchers have developed PIP@MIL-100(Fe), an organic metal-organic framework (MOF) that encapsulates PIP for breast cancer treatment.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis.

Introduction: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression.

Methods: In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors.

Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors.

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs.

The WNK1-ERK5 route plays a pathophysiological role in ovarian cancer and limits therapeutic efficacy of trametinib.

Background: The dismal prognosis of advanced ovarian cancer calls for the development of novel therapies to improve disease outcome. In this regard, we set out to discover new molecular entities and to assess the preclinical effectiveness of their targeting.

Methods: Cell lines, mice and human ovarian cancer samples were used.

Mapping Immune Correlates and Surfaceome Genes in Mutated Colorectal Cancers.

Despite the impressive results obtained with immunotherapy in several cancer types, a significant fraction of patients remains unresponsive to these treatments. In colorectal cancer (CRC), B-RafV600 mutations have been identified in 8-15% of the patients. In this work we interrogated a public dataset to explore the surfaceome of these tumors and found that several genes, such as GP2, CLDN18, AQP5, TM4SF4, NTSR1, VNN1, and CD109, were upregulated.

HER3 in cancer: from the bench to the bedside.

The HER3 protein, that belongs to the ErbB/HER receptor tyrosine kinase (RTK) family, is expressed in several types of tumors. That fact, together with the role of HER3 in promoting cell proliferation, implicate that targeting HER3 may have therapeutic relevance. Furthermore, expression and activation of HER3 has been linked to resistance to drugs that target other HER receptors such as agents that act on EGFR or HER2.