From the Gorgon's blood to Behring's Blutserumtherapie: A long path towards serum therapy.

At the end of the 19th century medicine was turned upside down by the development of serum therapy, a great therapeutic revolution as was vaccination a few years earlier. Many serums were developed, the most famous being the German doctor Emil von Behring's diphtheria serum, which saved countless children's lives from this dreadful disease. The discovery of the serum therapy principle, allowed by the progressive understanding of humoral immunity, occurred both in Germany and France, almost at the same time. Interestingly, this principle arose from two different intellectual paths, reviving the age-old opposition between mechanism and vitalism: while Behring came to this discovery reasoning as a chemist, French researchers Charles Richet and Jules Héricourt behaved as physiologists, focusing on the role of the host in the host-pathogen interaction. However, we should maybe consider that serum therapy history begins much earlier. Great forerunners must not be forgotten, especially researchers who investigated the field of immunity as soon as in the very beginning of the microbiological revolution; but also many people throughout centuries who tried to cure diseases with blood: as a transfer of blood serum, serum therapy also lies in the tradition of blood transfusion.

Quantum leap of monoclonal antibody (mAb) discovery and development in the COVID-19 era.

In recent years the global market for monoclonal antibodies (mAbs) became a multi-billion-dollar business. This success is mainly driven by treatments in the oncology and autoimmune space. Instead, development of effective mAbs against infectious diseases has been lagging behind. For years the high production cost and limited efficacy have blocked broader application of mAbs in the infectious disease space, which instead has been dominated for almost a century by effective and cheap antibiotics and vaccines. Only very few mAbs against RSV, anthrax, Clostridium difficile or rabies have reached the market. This is about to change. The development of urgently needed and highly effective mAbs as preventive and therapeutic treatments against a variety of pathogens is gaining traction. Vast advances in mAb isolation, engineering and production have entirely shifted the cost-efficacy balance. MAbs against devastating diseases like Ebola, HIV and other complex pathogens are now within reach. This trend is further accelerated by ongoing or imminent health crises like COVID-19 and antimicrobial resistance (AMR), where antibodies could be the last resort. In this review we will retrace the history of antibodies from the times of serum therapy to modern mAbs and lay out how the current run for effective treatments against COVID-19 will lead to a quantum leap in scientific, technological and health care system innovation around mAb treatments for infectious diseases.

Autologous serum therapy reduces the symptoms and antihistamine burden in patients with chronic urticaria.

Introduction: Autologous serum therapy (AST) is considered a potentially curative therapeutic option in the treatment of chronic urticaria, especially in the autoreactive type. Aim: To determine the ratio of patients with a positive autologous serum skin test (ASST) in chronic urticaria and the efficacy of AST. Material and methods: A total of 77 (29 male and 48 female) patients with chronic urticaria were enrolled in the study. The autologous serum skin test (ASST) was performed for all patients and the patients were classified into two groups: ASST positive and ASST negative. Intramuscular injection of AST was administered and the total severity score (TSS) of the urticaria was calculated weekly for ten weeks. The TSS was calculated for another ten weeks without AST. Results: There were 34 patients (11 men and 23 women) in the positive group and 43 (18 men and 25 women) in the negative group. Reduction of symptoms of urticaria begins in the fourth week of the study in both groups. At week 20, 21 (61.7%) patients of the ASST (+) group and 12 (27.2%) patients of the ASST (-) group showed complete clearance. The use of antihistamines decreased from 100% at baseline in both groups to 8.82% and 25.58% in the ASST (+) and ASST (-) groups, respectively, at the end of the study. Conclusions: AST is a low-cost, cost-effective and potentially curative treatment with no adverse effects in these patients. It can reduce the burden of antihistamines.

Expanding anti-venom strategies: Camelid polyclonal antibodies with high capacity to recognize snake venom.

Camelid immunoglobulins represent a unique facet of antibody biology, challenging conventional understandings of antibody diversification. IgG2 and IgG3 in particular are composed solely of heavy chains and exhibit a reduced molecular weight (90 kDa); their elongated complementarity determining region (CDR) loops play a pivotal role in their functioning, delving deep into enzyme active sites with precision. Serum therapy stands as the primary venom-specific treatment for snakebite envenomation, harnessing purified antibodies available in diverse forms such as whole IgG, monovalent fragment antibody (Fab), or divalent fragment antibody F (ab')2. This investigation looks into the intricacies of IgGs derived from camelid serum previously immunized with crotamine and crotoxin, toxins predominantly in Crotalus durissus venom, exploring their recognition capacity, specificity, and cross-reactivity to snake venoms and its toxins. Initially, IgG purification employed affinity chromatography via protein A and G columns to segregate conventional antibodies (IgG1) from heavy chain antibodies (IgG2 and IgG3) of camelid isotypes sourced from Lama glama serum. Subsequent electrophoretic analysis (SDS-PAGE) revealed distinct bands corresponding to molecular weight profiles of IgG's fractions representing isotypes in Lama glama serum. ELISA cross-reactivity assays demonstrated all three IgG isotypes' ability to recognize the tested venoms. Notably, IgG1 exhibited the lowest interactivity in analyses involving bothropic and crotalic venoms. However, IgG2 and IgG3 displayed notable cross-reactivity, particularly with crotalic venoms and toxins, albeit with exceptions such as PLA2-CB, showing reduced reactivity, and C. atrox, where IgGs exhibited insignificant reactivity. In Western blot assays, IgG2 and IgG3 exhibited recognition of proteins within molecular weight (≈15 kDa) of C. d. collilineatus to C. d. terrificus, with some interaction observed even with bothropic proteins despite lower reactivity. These findings underscore the potential of camelid heavy-chain antibodies, suggesting Lama glama IgGs as prospective candidates for a novel class of serum therapies. However, further investigations are imperative to ascertain their suitability for serum therapy applications.

Shibasaburo Kitasato (1853-1931): Pioneer of Japanese Medicine and Global Immunology Innovator.

Shibasaburo Kitasato (1853-1931), a pivotal figure in modern Japanese medicine, made groundbreaking contributions to bacteriology and immunology. His achievements include pure cultivation of the tetanus bacillus and the development of serum therapy, which continue to influence modern immunology and vaccination strategies. Kitasato established the Institute for Infectious Diseases in Japan, the Kitasato Institute, played a crucial role in establishing the Keio University School of Medicine, and served as the first president of the Japan Medical Association. His international collaboration with Robert Koch and Emil von Behring elevated Japan's status in global medical research. Kitasato's research philosophy emphasizes clinical applicability and passionate pursuit of effective topics, inspiring the generation of prominent Japanese medical researchers. This study highlights Kitasato's life, work, and enduring impact on medical research, education, and healthcare administration. Kitasato's legacy, commemorated on the new 1000-yen banknote in 2024, continues to serve as an inspiration for contemporary medical professionals worldwide.

Monoclonal antibodies for prophylactic and therapeutic use against viral infections.

Neutralizing antibodies play an essential part in antiviral immunity and are instrumental in preventing or modulating viral diseases. Polyclonal antibody preparations are increasingly being replaced by highly potent monoclonal antibodies (mAbs). Cocktails of mAbs and bispecific constructs can be used to simultaneously target multiple viral epitopes and to overcome issues of neutralization escape. Advances in antibody engineering have led to a large array of novel mAb formats, while deeper insight into the biology of several viruses and increasing knowledge of their neutralizing epitopes has extended the list of potential targets. In addition, progress in developing inexpensive production platforms will make antiviral mAbs more widely available and affordable.

The Pest Hospital: Memory, Vaccines, and Serum Therapy in Kansas City.

A medical narrative from a woman in her 90s describes her childhood bout with diphtheria in Kansas City, Missouri, apparently immediately after vaccination, her confinement in the "pest hospital," and her treatment with what she understood as a blood transfusion from a donor who was found through a radio appeal. In this essay, we trace the narrative back to the institutions, medical practices, and historical context, examining both the underlying history of medical practice and scientific understanding that is reflected in her experience and also the contexts of that history, including racial and religious attitudes.

Production and Functional Evaluation of Anti-Loxosceles Sera Raised by Immunizations of Rabbits with Mutated Recombinant Phospholipases-D.

Loxoscelism is the clinical condition triggered after the bite of spiders of the genus Loxosceles. The main species involved in accidents in South America are L. intermedia, L. laeta, and L. gaucho. The only specific treatment is the anti-Loxosceles serum produced with crude venoms. As phospholipases D (PLDs) trigger most of the effects observed in accidents, we developed and evaluated second-generation sera using mutated PLDs as antigens. Three isoforms of PLDs with site-directed mutations without biological activities were used for rabbit immunizations: D32A-E34A (L. gaucho), W230A (L. intermedia), and H12A-H47A (L. laeta). Sera were produced using crude venoms of three species of Loxosceles enriched with mutated recombinant PLDs (MIX) or using only mutated PLDs (REC). Immunizations stimulated the immune system from the second immunization with higher antibody production in the REC group. In vivo neutralization assays demonstrated that both sera reduced edema and dermonecrosis caused by Loxosceles intermedia crude venom. Follow-up of animals during the immunization protocols and in the neutralization assays demonstrated that the mutated proteins and the sera are safe. Results demonstrate the potential of using mutated recombinant PLDs in total or partial replacement of Loxosceles venoms in animal immunizations to produce anti-Loxosceles sera for treatments of Loxoscelism.

Engineering of single-domain antibodies for next-generation snakebite antivenoms.

Given the magnitude of the global snakebite crisis, strategies to ensure the quality of antivenom, as well as the availability and sustainability of its supply are under development by several research groups. Recombinant DNA technology has allowed the engineering of monoclonal antibodies and recombinant fragments as alternatives to conventional antivenoms. Besides having higher therapeutic efficacy, with broad neutralization capacity against local and systemic toxicity, novel antivenoms need to be safe and cost-effective. Due to the biological and physical chemical properties of camelid single-domain antibodies, with high volume of distribution to distal tissue, their modular format, and their versatility, their biotechnological application has grown considerably in recent decades. This article presents the most up-to-date developments concerning camelid single-domain-based antibodies against major toxins from snake venoms, the main venomous animals responsible for reported envenoming cases and related human deaths. A brief discussion on the composition, challenges, and perspectives of antivenoms is presented, as well as the road ahead for next-generation antivenoms based on single-domain antibodies.

History, challenges and perspectives on Loxosceles (brown spiders) antivenom production in Brazil.

Antivenom is the only effective therapy for treating any envenomation. Despite its obvious public health importance, the laborious process of procuring, distributing and controlling the quality of such immunobiologicals is being neglected. Brazil is fully self-sufficient in the production of antivenoms. Since the 1950s, Loxoscelism, a syndrome with an onset after a spider bite from specimens of the Loxosceles genus occurs, is considered a public health issue. The Brazilian history in developing antivenom therapy, its production hindrances, and other challenges are discussed in this paper, as well as some promising novelties that can improve production and processing of Loxosceles antivenom.