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International Journal of Molecular... Jul 2023To achieve the scheme of "magic bullets" in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific... (Review)
Review
To achieve the scheme of "magic bullets" in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific antigens, chemical linkers, and cytotoxic payloads that powerfully kill cancer cells. With the approval of ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), the therapeutic potentials of ADCs in breast cancer have come into the spotlight. Nearly 30 ADCs for breast cancer are under exploration to move targeted therapy forward. In this review, we summarize the presenting and emerging agents and targets of ADCs. The ADC structure and development history are also concluded. Moreover, the challenges faced and prospected future directions in this field are reviewed, which give insights into novel treatments with ADCs for breast cancer.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Antineoplastic Agents; Ado-Trastuzumab Emtansine; Immunoconjugates
PubMed: 37569276
DOI: 10.3390/ijms241511903 -
International Journal of Molecular... Mar 2024The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic... (Review)
Review
The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.
Topics: Humans; Omalizumab; Antibodies, Monoclonal, Humanized; Asthma; Hypersensitivity; Immunoglobulin E
PubMed: 38474304
DOI: 10.3390/ijms25053056 -
Cellular and Molecular Life Sciences :... Nov 2023Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Currently, standard treatment options for TNBC are limited to surgery, adjuvant... (Review)
Review
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Currently, standard treatment options for TNBC are limited to surgery, adjuvant chemotherapy, and radiotherapy. However, these treatment methods are associated with a higher risk of intrinsic or acquired recurrence. Antibody-drug conjugates (ADCs) have emerged as a useful and promising class of cancer therapeutics. ADCs, also known as "biochemical missiles", use a monoclonal antibody (mAb) to target tumor antigens and deliver a cytotoxic drug payload. Currently, several ADCs clinical studies are underway worldwide, including sacituzumab govitecan (SG), which was recently approved by the FDA for the treatment of TNBC. However, due to the fact that only a small portion of TNBC patients respond to ADC therapy and often develop resistance, growing evidence supports the use of ADCs in combination with other treatment strategies to treat TNBC. In this review, we described the current utilization of ADCs and discussed the prospects of ADC combination therapy for TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Combined Modality Therapy; Aggression; Antibodies, Monoclonal
PubMed: 37930428
DOI: 10.1007/s00018-023-04946-x -
Frontiers of Medicine Dec 2023The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 and its variants of concern (VOCs) has been ongoing for... (Review)
Review
The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.
Topics: Humans; Antibodies, Viral; Communicable Diseases, Emerging; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Antibodies, Neutralizing
PubMed: 38040914
DOI: 10.1007/s11684-023-1021-y -
Current Opinion in Rheumatology May 2024The approval of belimumab and anifrolumab has expanded the scope of treatment for systemic lupus erythematosus (SLE) patients. However, many patients remain refractory... (Review)
Review
PURPOSE OF REVIEW
The approval of belimumab and anifrolumab has expanded the scope of treatment for systemic lupus erythematosus (SLE) patients. However, many patients remain refractory to currently available therapies and suffer from drug toxicities. This review will discuss approved and target-specific therapeutics in development that bring hope for better SLE treatments.
RECENT FINDINGS
Since the last review on this subject in the journal, the FDA has approved anifrolumab and belimumab for SLE and lupus nephritis (LN), respectively. A fully humanized anti-CD20, obinutuzumab, met the primary end point in a phase II trial in LN. A Tyk2 inhibitor, deucravacitinib, and an antibody targeting plasmacytoid dendritic cells, litifilimab, met the primary end point in phase II trials in SLE and cutaneous lupus erythematosus (CLE). Ustekinumab and baricitinib met the primary end point in phase II but not in phase III trials.
SUMMARY
While many drug candidates which met the end points in phase II trials have failed phase III trials, the number of target-specific therapies for SLE has continued to expand.
Topics: Humans; Lupus Erythematosus, Systemic; Ustekinumab; Biological Therapy; Lupus Erythematosus, Cutaneous; Lupus Nephritis
PubMed: 38299618
DOI: 10.1097/BOR.0000000000001003 -
MAbs 2024Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and... (Review)
Review
Biparatopic antibodies (bpAbs) bind distinct, non-overlapping epitopes on an antigen. This unique binding mode enables new mechanisms of action beyond monospecific and bispecific antibodies (bsAbs) that can make bpAbs effective therapeutics for various indications, including oncology and infectious diseases. Biparatopic binding can lead to superior affinity and specificity, promote antagonism, lock target conformation, and result in higher-order target clustering. Such antibody-target complexes can elicit strong agonism, increase immune effector function, or result in rapid target downregulation and lysosomal trafficking. These are not only attractive properties for therapeutic antibodies but are increasingly being explored for other modalities such as antibody-drug conjugates, T-cell engagers and chimeric antigen receptors. Recent advances in bpAb engineering have enabled the construction of ever more sophisticated formats that are starting to show promise in the clinic.
Topics: Immunoconjugates; Antibodies, Bispecific; Epitopes; Receptors, Chimeric Antigen
PubMed: 38439551
DOI: 10.1080/19420862.2024.2310890 -
Current Oncology (Toronto, Ont.) Dec 2023Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel... (Review)
Review
Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody-drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer.
Topics: Humans; Female; Neoplasm Recurrence, Local; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Bevacizumab; Therapies, Investigational; Tumor Microenvironment
PubMed: 38248092
DOI: 10.3390/curroncol31010007 -
The Journal of Experimental Medicine Sep 2023Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses...
Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. Plasma neutralizing potency and breadth were similar between the two groups. By contrast, the absolute number of SARS-CoV-2-specific memory B cells was lower in the elderly. Antibody sequencing revealed that the SARS-CoV-2-specific elderly memory compartments were more clonal and less diverse. Notably, memory antibodies from the elderly preferentially targeted the ACE2-binding site on the RBD, while those from younger individuals targeted less accessible but more conserved epitopes. Nevertheless, individual memory antibodies elicited by booster vaccines in the elderly and younger individuals showed similar levels of neutralizing activity and breadth against SARS-CoV-2 variants. Thus, the relatively diminished protective effects of vaccination against serious disease in the elderly are associated with a smaller number of antigen-specific memory B cells that express altered antibody repertoires.
Topics: Aged; Humans; Memory B Cells; COVID-19; SARS-CoV-2; Vaccination; Antibodies; RNA, Messenger; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37368240
DOI: 10.1084/jem.20230668 -
Journal of Translational Medicine Oct 2023Antibody technology is widely used in the fields of biomedical and clinical therapies. Nonetheless, the complex in vitro expression of recombinant proteins, long... (Review)
Review
Antibody technology is widely used in the fields of biomedical and clinical therapies. Nonetheless, the complex in vitro expression of recombinant proteins, long production cycles, and harsh storage conditions have limited their applications in medicine, especially in clinical therapies. Recently, this dilemma has been overcome to a certain extent by the development of mRNA delivery systems, in which antibody-encoding mRNAs are enclosed in nanomaterials and delivered to the body. On entering the cytoplasm, the mRNAs immediately bind to ribosomes and undergo translation and post-translational modifications. This process produces monoclonal or bispecific antibodies that act directly on the patient. Additionally, it eliminates the cumbersome process of in vitro protein expression and extends the half-life of short-lived proteins, which significantly reduces the cost and duration of antibody production. This review focuses on the benefits and drawbacks of mRNA antibodies compared with the traditional in vitro expressed antibodies. In addition, it elucidates the progress of mRNA antibodies in the prevention of infectious diseases and oncology therapy.
Topics: Humans; RNA, Messenger; Pharmaceutical Preparations; Immunization, Passive; Antibodies, Bispecific; Recombinant Proteins; Immunotherapy
PubMed: 37794448
DOI: 10.1186/s12967-023-04553-1 -
Journal of Hematology & Oncology Dec 2023Antibody-drug conjugates (ADCs) have emerged as a novel therapeutic strategy that has successfully reached patient treatment in different clinical scenarios. ADCs are... (Review)
Review
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. In this article using data from approved ADCs, we evaluated all characteristics of these agents, including payload physicochemical properties, in vitro potency, drug antibody ratio (DAR), exposure-response relationships, and clinical development strategies. We suggest that compounds with best options for clinical development include those with optimal payload physicochemical properties and cleavable linkers that would lead to a bystander effect. These modalities can facilitate the development of ADCs in indications with low expression of the TAA. Early clinical development strategies including changes in the schedule of administration with more frequent doses are also discussed in the context of an efficient strategy. In conclusion, we highlight relevant aspects that are needed for the optimal development of ADCs in cancer, proposing options for improvement.
Topics: Humans; Immunoconjugates; Antibodies; Antineoplastic Agents; Neoplasms
PubMed: 38087293
DOI: 10.1186/s13045-023-01519-0