Drug repurposing of rimantadine for treatment of cancer.

Repurposing of approved drugs allows strong savings in time and investment. Rimantadine is an FDA-approved drug for prevention and treatment of influenza A infection. Patent US2021330605 describes the use of rimantadine, an adamantane derivative, for the treatment of melanoma, breast cancer and head and neck squamous cell carcinoma. Rimantadine inhibited proliferation of cell lines of melanoma, breast cancer, and head and neck squamous cell carcinoma, increased the survival of mice injected with cancer cell lines and restores the expression of MHC class I. Rimantadine has the potential to be used successfully in the treatment of head and neck squamous cell carcinoma.

Drug repurposing of mito-atovaquone for cancer treatment.

Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of Pneumocystis carinii pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-atovaquone has the potential to be used successfully in the treatment of various types of tumors.

Estrogens as a Possible Therapeutic Strategy for the Management of Neuroinflammation and Neuroprotection in COVID-19.

The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

Patenting trends in the pharmaceutical field of Mexican universities.

Aim: pharmaceutical patenting activity in developing countries, including Mexico, is unknown. Objective: determine the activity of pharmaceutical patents by Mexican universities. Method: using 'university' as keyword and A61K, A61P and C07 as International Patent Classification codes, was searched to generate a perspective of pharmaceutical patent applications by Mexican universities. Results: 227 patents (186 granted patents + 41 not-granted patents) were claimed in the period 2000-2018. The leading university was the National Autonomous University of Mexico, followed by the Instituto Politecnico Nacional, Universidad Autonoma de Nuevo León and Universidad Autonoma de Puebla. The pharmaceutical concerns addressed were led by the fields of infectious, cancer and diabetes. Conclusion: in Mexican universities, the licensing of pharmaceutical patents is still in its early stages.

Patenting trends by Mexican pharmaceutical companies.

Aim: the activity of patent claims by Mexican pharmaceutical companies is unknown. Objective: analyse the trend in patents of Mexican pharmaceutical companies. Method: a search for patents was carried out in the patent database of the Mexican Institute of Industrial Property, using the list of Mexican pharmaceutical companies belonging to the Mexican Association of Pharmaceutical Research Industries, and the codes A61K, A61P and C07 of the International Patent Classification. Results: the leading companies in patent applications were Liomont, Senosiain and RIMSA; however, Mexican pharmaceutical companies claim very few patents, only 266 patent applications in the period 2000-2020, with a technological factor with a value of zero, and a commercial factor of little value. Conclusion: Mexican pharmaceutical companies lack a robust patent system, without growth, and with a low percentage of patents with high commercial value.

Evaluación tecnológica y comercial de patentes universitarias a partir de la identificación de oportunidades comerciales en transferencia de tecnología / Technological and commercial evaluation of university patents based on the identification of commercial opportunities in technology transfer

Resumen Ante la transición a universidades emprendedoras, existe la tendencia a incrementar el patentamiento, aunque sin un estudio profundo del potencial comercial, por lo que el porcentaje de los productos que lo logran es muy bajo. El objetivo de esta investigación fue diseñar una estrategia de evaluación tecnológica y comercial de patentes universitarias a partir de la identificación de oportunidades en transferencia de tecnología (TT). Para ello, se examinaron 269 solicitudes de patente de la Benemérita Universidad Autónoma de Puebla (BUAP) y de la Universidad Autónoma del Estado de Morelos (UAEM), de acuerdo con la Clasificación Internacional de Patentes (CIP), en un periodo de 10 años (2009-2018), mediante 4 pasos: (a) construcción de la base de datos con la herramienta del Instituto Mexicano de Propiedad Intelectual, (b) identificación de las capacidades inventivas, a través de la Organización Mundial de la Propiedad Intelectual, (c) distribución por industrias de intensidad y oportunidad de mercado tecnológico, de acuerdo con la Organización para la Cooperación y el Desarrollo Económicos, y (d) análisis del comportamiento del mercado, mediante el estudio de las 36 solicitudes del área farmacéutica de ambas universidades. Los resultados mostraron que el 68.4 % de la BUAP y 75.6 % de la UAEM presentan un posicionamiento competitivo predominante en industrias de alta y mediana-alta tecnología. La ventaja de la herramienta propuesta es que permite reconocer la oportunidad del mercado tecnológico a partir de la construcción de escenarios relacionados con el comportamiento de la CIP.

Abstract Given the transition to entrepreneurial universities, there is a tendency to increase patenting, although without a deep study of the commercial potential. Therefore, the percentage of those developments that succeed is very low. The objective of this research was to develop a strategy for the technological and commercial evaluation of university patents, based on the identification of commercial opportunities in technology transfer (TT). Patent applications from the Benemerita Universidad Autonoma de Puebla (BUAP) and the Universidad Autonoma del Estado de Morelos (UAEM) were used for the study. The methodology consisted of the analysis of 269 patent applications in a period of 10 years 2009-2018, in accordance with the statistical International Patent Classification (IPC), through 4 steps: (a) construction of the patent database, with the use of the patent tool of the Mexican Institute of Intellectual Property, (b) identification of inventive capabilities, through the World Intellectual Property Organization, (c) distribution by industries of intensity and technological market opportunity, with the tool of the Organization for Economic Cooperation and Development, and (d) analysis of market behavior, through the study of the 36 applications of the pharmaceutical patent area, from both universities. The results showed that 68.4 % of BUAP and 75.6 % of UAEM reflected a predominantly competitive positioning in high technology and medium-high technology industries. The advantage of the proposed tool is that it allows the recognition of the technological market opportunity based on the construction of scenarios related to the IPC behavior.

Approaches for development of LAG-3 inhibitors and the promise they hold as anticancer agents.

INTRODUCTION: LAG-3 is considered to be the third point of immunological control in relation to clinical trials that address cancer treatment, only behind PD-1 and CTLA-4, due to its role as a suppressor of the immune response and enhancer of differentiation of Treg cells. AREAS COVERED: The authors focus on emphasizing the strategy of development of LAG-3 inhibitors to develop anticancer therapeutics, especially from the perspective of designing new monoclonal and bispecific antibodies against LAG-3. This article also covers details of patents and clinical trials of LAG-3 inhibitors reported in the literature. In addition, we highlight as future research challenges the design and development of peptides and small molecules as inhibitors of LAG-3 function. EXPERT OPINION: Three approaches have been used for the development of LAG-3 inhibitors, and they include inhibitory LAG-3 binding peptides and antagonist monoclonal and multispecific antibodies. These approaches include more than 100 clinical trials of 21 molecules that bind to LAG-3 and block its binding to MHC II. However, these approaches do not cover the design and development of peptides and small molecules that could inhibit the function of LAG-3, for which it is necessary to develop new alternatives that cover this gap.

Pharmaceutical agents for the treatment of Chagas disease: patenting trends in the 2016-2021 period.

American trypanosomiasis is a neglected tropical disease and an endemic problem in 21 Latin American countries, whose treatment relies on only two US FDA-approved drugs: benznidazole and nifurtimox. Patent literature reveals vital information on new trends in therapies for various diseases, including Chagas disease. The authors used the patent databases of the world's major patent offices to generate an overview of patent trends related to the treatment of Chagas disease. A total of 50 patent families were collected and grouped as 'small molecules', 'pharmaceutical compositions of known compounds' and vaccines. From the results and interpretation, it can be concluded that the treatment of Chagas disease receives little attention in the field of patents and that the upward trend is minimal.

Drug repurposing of adapalene for melanoma treatment.

Cancer drug repurposing is an attractive approach that leads to savings in time and investment. Adapalene, the first medical application of which was for the treatment of acne, has been described as a repurposing drug for the treatment of various types of cancer. Patent application CN111329851 describes the use of adapalene for the treatment of melanoma, by assays carried out on melanoma cell lines. Adapalene demonstrated antiproliferative activity in melanoma cell lines via S-phase arrest-dependent apoptosis mediated by DNA damage through an increase in the expression of p-ATM and p-chk2 and a decrease in the expression of p-BRCA1 and Rad51. Even though no evidence on efficacy and efficiency is shown in preclinical and clinical studies, CN111329851 patent shows that adapalene may be a repurposing drug for the treatment of melanoma.

Small-molecule inhibitor PD-1/PD-L1 interaction for colorectal cancer treatment.

Inhibition of the PD-1/PD-L1 pathway is a target for the development of new therapies. US10710986 patent describes a small molecule that targets PDL-1/PD-1 interactions and triggers antitumor activity against colorectal cancer. However, it does not describe biological assays that allow us to suppose that this small molecule may be active in other types of cancer. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this compound surpasses the action of therapy in cancer.

Treatment of solid tumors using bispecific anti-PDL-1/ICOS antibody.

PD-L1 and ICOS are immune control points in cancer and their presence in cancer tends to have a poor prognosis. WO2019122882 patent describes a bispecific antibody that targets PDL-1/ICOS with the potential application of cancer treatment. WO2019122882 patent describes a bispecific antibody with antitumor efficacy in CT26 model through of the depletion of TReg cells and improved ratio of CD8+ T cells: TReg in tumor microenvironment. The anti-PDL-1/ICOS antibody is new; however, only preclinical assays are shown using colon carcinoma model. So far, there are no reports of clinical trials to evaluate the safety, toxicity and efficacy, but it will be of great interest to analyze in the future if this antibody surpasses the action of the combinatorial therapy in cancer.

Bispecific anti-OX40/5T4 antibodies for cancer treatment.

OX40 and 5T4 are molecules that play a role in T-cell expansion and cytoskeleton's disruption in cancer, respectively. US2019161555 patent describes a bispecific antibody that targets OX40/5T4 with the potential application of cancer treatment. The method of analysis of the US201916155 patent consisted of claim's analysis, as well as the chemical/biological information's analysis of the bispecific antibody. The patent includes independent claims related to bispecific antibodies that bind to OX40/5T4, DNA encoding the antibodies, a vector that harbors the DNA, a host cell that contains the vector, a pharmaceutical composition containing a pharmaceutically effective amount of the antibodies, medical use of the antibodies, use of the antibodies in the treatment or prevention of neoplastic disorders and a method of treating neoplastic disorders. Bispecific antibodies that target OX40/5T4 can activate IL-2 secretion in CD4+ T cells.

OX40 agonists for cancer treatment: a patent review.

INTRODUCTION: OX40 is an immune checkpoint in cancer and its presence in cancer is a good prognosis, making it a highly relevant target for the development of new immunotherapies. AREAS COVERED: The patent literature reveals vital information on new trends in cancer therapies. The authors used the patent databases of the six major patent offices in the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Office of Intellectual Property of China and Korean Intellectual Property Office, to generate a panorama of patents related to OX40 agonists. Specific patents have been grouped into innovative patents and adoption patents. EXPERT OPINION: An increasing trend in the development of OX40 agonists in cancer, particularly in the years 2018 and 2019. United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986,178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists.

Neurophysiological Mechanisms Related to Pain Management in Bone Tumors.

BACKGROUND: Primary and metastatic bone tumor incidence has increased in the previous years. Pain is a common symptom and is one of the most important related factors to the decrease of quality of life in patients with bone tumor. Different pain management strategies are not completely effective and many patients afflicted by cancer pain cannot be controlled properly. In this sense, we need to elucidate the neurophysiology of cancer-induced pain, contemplating other components such as inflammation, neuropathies and cognitive components regarding bone tumors, and thus pave the way for novel therapeutic approaches in this field. AIM: This study aims to identify the neurophysiology of the mechanisms related to pain management in bone tumors. METHODS: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index to get information about the neurophysiology mechanisms related to pain management in bone tumors. RESULTS: The central and peripheral mechanisms that promote bone cancer pain are poorly understood. Studies have shown that bone cancer could be related to neurochemicals produced by tumor and inflammatory cells, coupled with peripheral sensitization due to nerve compression and injury caused by tumor growth. The activity of mesolimbic dopaminergic neurons, substance P, cysteine/ glutamate antiporter, and other neurochemical dynamics brings us putative strategies to suggest better and efficient treatments against pain in cancer patients. CONCLUSION: Cancer-induced bone pain could include neuropathic and inflammatory pain, but with different modifications to the periphery tissue, nerves and neurochemical changes in different neurological levels. In this sense, we explore opportunity areas in pharmacological and nonpharmacological pain management, according to pain-involved mechanisms in this study.

Bispecific anti-PD-1/CTLA-4 antibody for advanced solid tumors.

PD-1 and CTLA-4 are checkpoint inhibitors of the immune response in cancer, making them the target molecules for the development of therapeutic antibodies. US2019161548 patent describes a bispecific antibody capable of specifically binding to PD-1 and CTLA-4 that induced the proliferation and activation of CD8+ cells, as well as the expression of induclble co-stimulator in CD4+ T cells. Clinical trials to evaluate safety, dose-limiting toxicities and maximum tolerated/administered dose are still in the patient recruitment phase, but it will be of great interest to the scientific and medical community to know if the first bispecific anti-PD-1/CLTA-4 antibody, exceeds expectations and exceeds action of the combination of nivolumab and epilimumab in the treatment of cancer.

Bispecific anti-PD-L1/PD-1 antibodies for advanced solid tumors: a patent evaluation of US2019010232.

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.

Bispecific anti-PD-1/LAG-3 antibodies for treatment of advanced or metastatic solid tumors: a patent evaluation of US2018326054.

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.

Treatment of cancer with an anti-KIR antibody: a patent evaluation of US9879082 and US2018208652.

Introduction: KIR is an inhibitory receptor expressed by natural killer cells that suppress the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of KIR and consequently improving the immune response in the various types of cancer. Authors of US9879082 and US2018208652 patents propose a method to eradicate cancer that utilizes anti-KIR antibody.Areas covered: US9879082 and US2018208652 patents describe an anti-KIR antibody, a pharmaceutical composition that contains it, and their application for cancer treatment, particularly, multiple myeloma and acute myeloid leukemia. Anti-KIR antibody is used to a dosage of 0.0003-3 mg antibody/kg patient weight, and is suspended in an isotonic solution consisting of sodium phosphate, sucrose, NaCl, and polysorbate 80.Expert opinion: The results of the clinical trials only support trials regarding the pharmacokinetic, pharmacodynamic, safety, and tolerability. In addition, these results demonstrate that treatment with the anti-KIR antibody can induce an antitumor response in cancer patients.

Cancer combinatorial immunotherapy using etigilimab and nivolumab: a patent evaluation of WO2018102536.

Introduction: TIGIT is an inhibitory receptor expressed by lymphocytes that suppresses the immune response against tumor cells. There is a great need to discover and develop new therapies focused on inhibiting the action of TIGIT and consequently improving the immune response in the various types of cancer. Authors of WO2018102536 patent propose a method to eradicate cancer utilizes anti-TIGIT antibody, etigilimab, in combination with anti-PD-1/PD-L1 antibody, nivolumab.Areas covered: WO2018102536 patent describes a method of cancer combinatorial treatment consisting of the utilization of either a pharmaceutical cocktail containing anti-TIGIT and an anti-PD-L1 antibody.Expert opinion: The results of the clinical trials only support trials regarding the tolerability of therapy with etigilimab, but does not show data related to the combined use of etigilimab and nivolumab.

Bispecific anti-OX40/CTLA-4 antibodies for advanced solid tumors: a patent evaluation of WO2018202649.

Introduction: OX40 is a potent costimulatory receptor of the immune response in various types of cancer and has been used as a target for the generation of agonists of its function. Authors of WO2018202649 patent propose a method to eradicate cancer using a bispecific antibodies against OX40/CTLA-4.Areas covered: WO2018202649 patent describes several bispecific antibodies capable of specifically binding to OX40 and CTLA-4 that target regulatory T cells in the tumor microenvironment.Expert opinion: WO2018202649 patent demonstrates that bispecific antibodies against OX40/CTLA-4 have anti-tumor activity against colon, pancreatic and bladder cancer, and that there is a synergistic action with anti-PD-1 antibodies for the treatment of colon cancer. However, there is no evidence to conclude that bispecific antibodies can be used in cancers other than colon, pancreas and bladder. Likewise, the patent only describes the application in combinatorial therapy with anti-PD-1 antibodies, without presenting data relative to the combination with other immunotherapeutic agents against other checkpoint targets.