Human Antibody Production in Transgenic Animals

Brüggemann, Marianne; Osborn, Michael J.; Ma, Biao; Hayre, Jasvinder; Avis, Suzanne; Lundstrom, Brian; Buelow, Roland

doi:10.1007/s00005-014-0322-x

Cited by 106 publications

(70 citation statements)

References 66 publications

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“…The great achievement of fully human monoclonal antibodies using transgenic mice allowed a remarkable opportunities for treatment of several hematological malignances [31]. Recently, fully-human monoclonal antibody anti-CD123, a surface marker which is overexpressed in a variety of hematological disorders, including in an acute myeloid leukemia (AML) enabled kill leukemic cells in vitro ADCC assays, the experiment was done both with cell lines and with patient-derived AML blasts [32].…”

Section: Fully Human Antibodiesmentioning

confidence: 99%

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

Yirga¹,

Lin²,

Huang³

et al. 2019

J Leuk

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Advancement of monoclonal antibodies (Mabs) to be accepted as a therapy has long history. This article describes the dramatic developmental trend of therapeutic antibody technology and their significant role for treatment of leukemia-lymphoma at the current time. The therapeutic Mab technology development from murine (mouse origin) to fully human resulted in low immunogenicity and high quality Mabs. Chemotherapy is standard care for leukemialymphoma treatments. However, it is associated with high toxicities (side effects), painful and relatively ineffective against certain leukemia-lymphoma subtypes. The remarkable contribution of Von Behring, Paul Ehrlich and the discovery of hybridoma technology marked the beginning of antibodies for therapeutic applications. Rituximab is the first Mab approved by Food and Drug Administration against B-cell malignancies. Today, a number of effective Mabs targeting leukemia and lymphoma were approved and successfully developed. The Mab therapeutic phenomena in the body (also called war in the blood) has various mechanism of actions. In recent years, Mab against leukemialymphoma achieved significantly therapeutic outcomes, eventually this led to traditional chemotherapy treatment free era. We also reviewed that, the therapeutic efficacy of Mabs against leukemia-lymphoma as compared antibody alone and antibody conjugated with potent chemotherapy or cytotoxic drugs. This article extends our understanding of advancements in therapeutic Mabs technology and provides new insights of Mab leukemia-lymphomas therapy. We also encourage further more studies for Mab based diagnostics, treatments of leukemia and lymphomas.

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Section: Fully Human Antibodiesmentioning

confidence: 99%

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

Yirga¹,

Lin²,

Huang³

et al. 2019

J Leuk

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“…Most advanced are fully human immunoglobulin transgenic animals harboring completely human V(D)J regions and with endogenous murine immunoglobulin sequences inactivated. Immunization of these animals generates a diverse antibody response against a number of pathogens [88]. Although these animals have not yet been used in the context of malaria, isolation of mAbs or polyclonal sera derived from these animals will better represent the diversity of human immunoglobulins raised against the relevant human pathogen.…”

Section: Current Strategies To Identify and Validate Novel Pe Vaccine Tmentioning

confidence: 99%

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

2016

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Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. Malaria continues to cause significant morbidity and mortality despite renewed and concerted efforts to eliminate the causative agents, parasites of the genus Plasmodium. These efforts have largely focused on control of the Anopheles mosquito vectors, and antimalarial drug treatment of symptomatic infected individuals. The 214 million new malaria infections and 438,000 deaths due to malaria in 2015 were disproportionately borne by low income countries where malaria is endemic, and declines in malaria infections since 2000 have been slowest in countries with low resource availability and high malaria burden [1]. In the fight against malaria, effective vaccines preventing both disease and transmission will be important tools to achieve WHO goals of a 90% reduction in disease burden by 2030 [1,2]. In humans, malaria is caused predominantly by the parasite species Plasmodium falciparum and Plasmodium vivax, with the remainder of infections caused by three additional parasite species, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi [1].Malaria parasite transmission occurs when a Plasmodium-infected Anopheles mosquito bites and by probing the skin for a blood meal, deposits motile sporozoite stages into the host. Sporozoites pass through the dermis using active motility, enter a capillary and then rapidly home to the liver. Once in the liver sporozoites enter the parenchyma and infect hepatocytes, wherein they then transmogrify into liver stages, which grow, replicate and ultimately differentiate into tens of thousands of first-generation merozoites. Merozoites of human malaria parasites emerge from the liver into the blood stream 7-10 days after transmission, where they undergo cyclic erythrocytic infection and intraerythrocytic replication. This blood-stage infection is responsible for all mortality and clinical symptoms of malaria, as well as infection of a new mosquito vector by sexual stage parasites for onward transmission [3,4]. Stages prior to blood-stage infection (i.e., the sporozoite and liver stages) are collectively known as preerythrocytic (PE) stages of infection and vaccine candidates targeting these stages are collectively termed PE vaccines. By preventing progression to ...

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“…Since then, advances in genetic engineering technologies allowed for the first transgenic mice strains that express fully human antibodies 6,7 . Today, many new transgenic animal models have been developed including rodents, chickens, rabbits and cows 8 . These animal models have been used extensively for the discovery of monoclonal antibodies (mAbs) 9 , tolerance studies 10 and more recently for modelling human antibody responses to vaccine candidates 3,4 .…”

Section: Introductionmentioning

confidence: 99%

Comparisons of the antibody repertoires of a humanized rodent and humans by high throughput sequencing

Joyce

Burton

Briney

2019

Preprint

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The humanization of animal model immune systems by genetic engineering has shown great promise for antibody discovery, tolerance studies and for the evaluation of vaccines. Assessment of the baseline antibody repertoire of unimmunized model animals will be useful as a benchmark for future immunization experiments. We characterized the heavy chain and kappa chain antibody repertoires of a model animal, the OmniRat, by high throughput antibody sequencing and made use of two novel datasets for comparison to human repertoires. Intra-animal and inter-animal repertoire comparisons reveal a high level of conservation in antibody diversity between the lymph node and spleen and between members of the species. Multiple differences were found in both the heavy and kappa chain repertoires between OmniRats and humans including gene segment usage, CDR3 length distributions, class switch recombination, somatic hypermutation levels and in features of V(D)J recombination. The Inference and Generation of Repertoires (IGoR) software tool was used to model recombination in VH regions which allowed for the quantification of some of these differences. Diversity estimates of the OmniRat heavy chain repertoires almost reached that of humans, around two orders of magnitude less. Despite variation between the species repertoires, a high frequency of OmniRat clonotypes were also found in the human repertoire. These data give insights into the development and selection of humanized animal antibodies and provide actionable information for use in vaccine studies.

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Human Antibody Production in Transgenic Animals

Cited by 106 publications

References 66 publications

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

Comparisons of the antibody repertoires of a humanized rodent and humans by high throughput sequencing

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