Antibody-Drug Conjugates in Breast Cancer: A Comprehensive Review of How to Selectively Deliver Payloads.

Antibody-drug conjugates (ADCs) have surfaced as a promising group of anticancer agents employing the precise targeting capacity of monoclonal antibodies to transport highly effective cytotoxic payloads. Compared to conventional chemotherapy, they aim to selectively eradicate cancer cells while minimizing off-target toxicity on healthy tissues. An increasing body of evidence has provided support for the efficacy of ADCs in treating breast cancer across various contexts and tumor subtypes, resulting in significant changes in clinical practice. Nevertheless, unlocking the full potential of these therapeutic agents demands innovative molecular designs to address complex clinical challenges, including drug resistance, tumor heterogeneity, and treatment-related adverse events. This thorough review provides an in-depth analysis of the clinical data on ADCs, offering crucial insights from pivotal clinical trials that assess the efficacy of ADCs in diverse breast cancer settings. This aids in providing a comprehensive understanding of the current state of ADCs in breast cancer therapy, while also providing valuable perspectives for the future.

Adverse events of antibody-drug conjugates on the ocular surface in cancer therapy.

Antibody-drug conjugates consist of a monoclonal antibody attached to a cytotoxic therapeutic molecule by a connector. This association allows a highly specific therapy, which increases their effectiveness and decreases their potential toxicity. This new therapy emerged approximately 20 years ago; since then, numerous combinations have appeared in the field of treatment-related neoplasms as an alternative for patients who do not achieve good results with conventional treatment options. Adverse effects of these drugs on the ocular surface are frequent and varied. Their prevalence ranges from 20 to 90% depending on the drug and administration condition, probably due to multiple receptor-mediated factors or mechanisms not mediated by specific receptors, such as macropinocytosis. These adverse events can greatly limit patients' comfort; thus, the objectives of this article were, in the first place, to compile the information currently available on different types of adverse effects of antibody-drug conjugates on the ocular surface, including pathophysiology, prevalence, and treatment, and in second place, to contribute to the correct identification and management of these events, which will result in a lower rate of cessation of treatment, which is necessary for the survival of candidate patients.

HER2-Directed Therapy in Advanced Breast Cancer: Benefits and Risks.

Around 20% of breast cancers are associated with amplification or overexpression of human epidermal growth factor receptor 2 (HER2). In this setting, anti-HER2-targeted agents are the cornerstone of cancer therapeutic strategies. This includes monoclonal antibodies, tyrosine kinase inhibitors (TKIs) and, recently, antibody-drug conjugates (ADCs). With the advent of these new alternatives, the decision-making process has become more complex, especially with regard to the treatment sequence possibilities. In spite of the fact that overall survival has significantly improved accordingly, resistance to treatment remains a challenge in HER2-positive breast cancer. The introduction of new agents has created awareness regarding new potential specific adverse events, and consequently, their increasing application pose major challenges in daily patient care. This review describes the therapeutic landscape for HER2-positive advanced breast cancer (ABC) and evaluates its benefits and risks in the clinical setting.

Antibody-drug conjugate as targeted therapeutics against hepatocellular carcinoma: preclinical studies and clinical relevance.

An antibody-drug conjugate (ADC) is an advanced chemotherapeutic option with immense promises in treating many tumor. They are designed to selectively attack and kill neoplastic cells with minimal toxicity to normal tissues. ADCs are complex engineered immunoconjugates that comprise a monoclonal antibody for site-directed delivery and cytotoxic payload for targeted destruction of malignant cells. Therefore, it enables the reduction of off-target toxicities and enhances the therapeutic index of the drug. Hepatocellular carcinoma (HCC) is a solid tumor that shows high heterogeneity of molecular phenotypes and is considered the second most common cause of cancer-related death. Studies show enormous potential for ADCs targeting GPC3 and CD24 and other tumor-associated antigens in HCC with their high, selective expression and show potential outputs in preclinical evaluations. The review mainly highlights the preclinical evaluation of different antigen-targeted ADCs such as MetFab-DOX, Anti-c-Met IgG-OXA, Anti CD 24, ANC-HN-01, G7mab-DOX, hYP7-DCand hYP7-PC, Anti-CD147 ILs-DOX and AC133-vcMMAF against hepatocellular carcinoma and its future relevance.

HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer.

PURPOSE: Knowledge on whether low expressions of HER2 have prognostic impact in early-stage breast cancer (BC) and on its response to current chemotherapy protocols can contribute to medical practice and development of new drugs for this subset of patients, changing treatment paradigms. This study aims to evaluate the impact of HER2-low status on response to neoadjuvant chemotherapy (NACT) and survival outcomes in early-stage HER2-negative BC. METHODS: Records from all BC patients treated with NACT from January 2007 to December 2018 in a single cancer center were retrospectively reviewed. HER2-negative (immunohistochemistry [IHC] 0, + 1, or + 2 non-amplified by in situ hybridization [ISH]) patients were included. HER2-low was defined by IHC + 1 or + 2 ISH non-amplified and HER2-0 by IHC 0. The coprimary objectives were to compare pathological complete response (pCR) and relapse-free survival (RFS) between luminal/HER2-low versus luminal/HER2-0 populations and between triple negative (TNBC)/HER2-low versus TNBC/HER2-0. RESULTS: In total, 855 HER2-negative patients were identified. The median follow-up was 59 months. 542 patients had luminal subtype (63.4%) and 313 had TNBC (36.6%). 285 (33.3%) were HER2-low. Among luminal patients, 145 had HER2 IHC + 1 (26.8%) and 91 had IHC + 2/ISH non-amplified (16.8%). In TNBC, 36 had HER2 IHC + 1 (11.5%) and 13 had IHC + 2/ISH non-amplified (4.2%). Most patients had locally advanced tumors, regardless of subtype or HER2-low status. For luminal disease, pCR was achieved in 13% of HER2-low tumors versus 9.5% of HER2-0 (p = 0.27). Similarly, there was no difference in pCR rates among TNBC: 51% versus 47% in HER2-low versus HER2-0, respectively (p = 0.64). HER2-low was also not prognostic for RFS, with 5-year RFS rates of 72.1% versus 71.7% (p = 0.47) for luminal HER2-low/HER2-0, respectively, and 75.6% versus 70.8% (p = 0.23) for TNBC HER2-low/HER2-0. CONCLUSION: Our data does not support HER2-low as a biologically distinct BC subtype, with no prognostic value on survival outcomes and no predictive effect for pCR after conventional NACT.

Antibody-drug conjugates: the new generation of biotechnological therapies against cancer.

Therapeutic antibodies are recombinant proteins used in the treatment of cancer. There is a new generation of monoclonal antibodies with activity against cancer cells, known as antibody-drug conjugates. These molecules are made up of three elements: a monoclonal antibody, a highly potent cytotoxic drug, and a chemical linker that binds them together. The antibody recognizes tumor antigens, thereby allowing targeted delivery of the cytotoxic agent to cancer cells. After recognizing its antigen, the antibody-drug conjugate is endocytosed by the target cells, where the protein fraction is degraded into lysosomes, releasing the cytotoxic drug. This article reviews antibody-drug conjugates general characteristics and describes the clinical evidence of efficacy and safety of the first four approved by regulatory agencies in the United States and Europe.

Los anticuerpos terapéuticos son proteínas recombinantes empleadas en el tratamiento del cáncer. Existe una nueva ­generación de anticuerpos monoclonales con actividad contra las células cancerosas, conocidos como anticuerpos conjugados a fármacos. Estas moléculas están integradas por tres elementos: un anticuerpo monoclonal, un fármaco citotóxico con alta potencia y un enlazador químico que los une. El anticuerpo reconoce antígenos tumorales, por lo que permite la entrega dirigida del agente citotóxico hacia las células cancerosas. Tras el reconocimiento de su antígeno, el anticuerpo conjugado a fármaco es endocitado por las células blanco, donde se induce la degradación lisosomal de la fracción proteica y se libera el fármaco citotóxico. En el presente artículo se revisan las características generales de los anticuerpos conjugados a fármacos y se describe la evidencia clínica de la eficacia y seguridad de los primeros cuatro aprobados por las agencias reguladoras de Estados Unidos y Europa.

Anticuerpos conjugados a fármaco: la nueva generación de terapias biotecnológicas contra el cáncer / Antibody-drug conjugates: the new generation of biotechnological therapies against cancer

Resumen Los anticuerpos terapéuticos son proteínas recombinantes empleadas en el tratamiento del cáncer. Existe una nueva generación de anticuerpos monoclonales con actividad contra las células cancerosas, conocidos como anticuerpos conjugados a fármacos. Estas moléculas están integradas por tres elementos: un anticuerpo monoclonal, un fármaco citotóxico con alta potencia y un enlazador químico que los une. El anticuerpo reconoce antígenos tumorales, por lo que permite la entrega dirigida del agente citotóxico hacia las células cancerosas. Tras el reconocimiento de su antígeno, el anticuerpo conjugado a fármaco es endocitado por las células blanco, donde se induce la degradación lisosomal de la fracción proteica y se libera el fármaco citotóxico. En el presente artículo se revisan las características generales de los anticuerpos conjugados a fármacos y se describe la evidencia clínica de la eficacia y seguridad de los primeros cuatro aprobados por las agencias reguladoras de Estados Unidos y Europa.

Abstract Therapeutic antibodies are recombinant proteins used in the treatment of cancer. There is a new generation of monoclonal antibodies with activity against cancer cells, known as antibody-drug conjugates. These molecules are made up of three elements: a monoclonal antibody, a highly potent cytotoxic drug, and a chemical linker that binds them together. The antibody recognizes tumor antigens, thereby allowing targeted delivery of the cytotoxic agent to cancer cells. After recognizing its antigen, the antibody-drug conjugate is endocytosed by the target cells, where the protein fraction is degradated into lysosomes, releasing the cytotoxic drug. This article reviews antibody-drug conjugates general characteristics and describes the clinical evidence of efficacy and safety of the first four approved by regulatory agencies in the United States and Europe.

Marine drugs for cancer: surfacing biotechnological innovations from the oceans

This review will discuss the contributions of marine natural molecules, a source only recently found to have pharmaceutical prospects, to the development of anticancer drugs. Of the seven clinically utilized compounds with a marine origin, four are used for the treatment of cancer. The development of these drugs has afforded valuable knowledge and crucial insights to meet the most common challenges in this endeavor, such as toxicity and supply. In this context, the development of these compounds will be discussed herein to illustrate, with successful examples provided by cytarabine, trabectedin, eribulin and brentuximab vedotin, the steps involved in this process as well as the scientific advances and technological innovation potential associated with developing a new drug from marine resources.