Статті в журналах: "Human monoclonal antibodies (humAbs)"

1

Broering, Teresa J., Kerry A. Garrity, Naomi K. Boatright, Susan E. Sloan, Frantisek Sandor, William D. Thomas, Gyongyi Szabo, Robert W. Finberg, Donna M. Ambrosino, and Gregory J. Babcock. "Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus." Journal of Virology 83, no. 23 (September 16, 2009): 12473–82. http://dx.doi.org/10.1128/jvi.01138-09.

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ABSTRACT Nearly all livers transplanted into hepatitis C virus (HCV)-positive patients become infected with HCV, and 10 to 25% of reinfected livers develop cirrhosis within 5 years. Neutralizing monoclonal antibody could be an effective therapy for the prevention of infection in a transplant setting. To pursue this treatment modality, we developed human monoclonal antibodies (HuMAbs) directed against the HCV E2 envelope glycoprotein and assessed the capacity of these HuMAbs to neutralize a broad panel of HCV genotypes. HuMAb antibodies were generated by immunizing transgenic mice containing human antibody genes (HuMAb mice; Medarex Inc.) with soluble E2 envelope glycoprotein derived from a genotype 1a virus (H77). Two HuMAbs, HCV1 and 95-2, were selected for further study based on initial cross-reactivity with soluble E2 glycoproteins derived from genotypes 1a and 1b, as well as neutralization of lentivirus pseudotyped with HCV 1a and 1b envelope glycoproteins. Additionally, HuMAbs HCV1 and 95-2 potently neutralized pseudoviruses from all genotypes tested (1a, 1b, 2b, 3a, and 4a). Epitope mapping with mammalian and bacterially expressed proteins, as well as synthetic peptides, revealed that HuMAbs HCV1 and 95-2 recognize a highly conserved linear epitope spanning amino acids 412 to 423 of the E2 glycoprotein. The capacity to recognize and neutralize a broad range of genotypes, the highly conserved E2 epitope, and the fully human nature of the antibodies make HuMAbs HCV1 and 95-2 excellent candidates for treatment of HCV-positive individuals undergoing liver transplantation.

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Mukherjee, Jean, Kerry Chios, Dianne Fishwild, Deborah Hudson, Susan O'Donnell, Stephen M. Rich, Arthur Donohue-Rolfe, and Saul Tzipori. "Human Stx2-Specific Monoclonal Antibodies Prevent Systemic Complications of Escherichia coli O157:H7 Infection." Infection and Immunity 70, no. 2 (February 2002): 612–19. http://dx.doi.org/10.1128/iai.70.2.612-619.2002.

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ABSTRACT Hemolytic-uremic syndrome (HUS) is a serious complication predominantly associated with infection by enterohemorrhagic Escherichia coli (EHEC), such as E. coli O157:H7. EHEC can produce Shiga toxin 1 (Stx1) and/or Shiga toxin 2 (Stx2), both of which are exotoxins comprised of active (A) and binding (B) subunits. In piglets and mice, Stx can induce fatal neurological symptoms. Polyclonal Stx2 antiserum can prevent these effects in piglets infected with the Stx2-producing E. coli O157:H7 strain 86-24. Human monoclonal antibodies (HuMAbs) against Stx2 were developed as potential passive immunotherapeutic reagents for the prevention and/or treatment of HUS. Transgenic mice bearing unrearranged human immunoglobulin (Ig) heavy and κ light chain loci (HuMAb___Mouse) were immunized with formalin-inactivated Stx2. Thirty-seven stable hybridomas secreting Stx2-specific HuMAbs were isolated: 33 IgG1κ A-subunit-specific and 3 IgG1κ and 1 IgG3κ B-subunit-specific antibodies. Six IgG1κ A-subunit-specific (1G3, 2F10, 3E9, 4H9, 5A4, and 5C12) and two IgG1κ B-subunit-specific (5H8 and 6G3) HuMAbs demonstrated neutralization of >95% activity of 1 ng of Stx2 in the presence of 0.04 μg of HuMAb in vitro and significant prolongation of survival of mice given 50 μg of HuMAb intraperitoneally (i.p.) and 25 ng of Stx2 intravenously. When administered i.p. to gnotobiotic piglets 6 or 12 h after infection with E. coli O157:H7 strain 86-24, HuMAbs 2F10, 3E9, 5H8, and 5C12 prolonged survival and prevented development of fatal neurological signs and cerebral lesions. The Stx2-neutralizing ability of these HuMAbs could potentially be used clinically to passively protect against HUS development in individuals infected with Stx-producing bacteria, including E. coli O157:H7.

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Wang, Jianmin, Zhe Chen, Linlin Bao, Weijia Zhang, Ying Xue, XingHuo Pang, Xi Zhang, Chuan Qin, and Qi Jin. "Characterization of Two Human Monoclonal Antibodies Neutralizing Influenza A H7N9 Viruses." Journal of Virology 89, no. 17 (June 10, 2015): 9115–18. http://dx.doi.org/10.1128/jvi.01295-15.

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H7N9 was a cause of significant global health concern due to its severe infection and approximately 35% mortality in humans. By screening a Fab antibody phage library derived from patients who recovered from H7N9 infections, we characterized two human monoclonal antibodies (HuMAbs), HNIgGD5 and HNIgGH8. The epitope of these two antibodies was dependent on two residues in the receptor binding site at positions V186 and L226 of the hemagglutinin glycoprotein. Both antibodies possessed high neutralizing activity.

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Wang, Yang, Rianne Esquivel, Seleeke Flingai, Zachary A. Schiller, Aurélie Kern, Sangya Agarwal, Jacqueline Chu, et al. "Anti-OspA DNA-Encoded Monoclonal Antibody Prevents Transmission of Spirochetes in Tick Challenge Providing Sterilizing Immunity in Mice." Journal of Infectious Diseases 219, no. 7 (November 21, 2018): 1146–50. http://dx.doi.org/10.1093/infdis/jiy627.

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AbstractWe recently developed anti-OspA human immunoglobulin G1 monoclonal antibodies (HuMAbs) that are effective in preventing Borrelia transmission from ticks in a murine model. Here, we investigated a novel approach of DNA-mediated gene transfer of HuMAbs that provide protection against Lyme disease. Plasmid DNA-encoded anti-OspA HuMAbs inoculated in mice achieved a serum antibody concentration of >6 μg/mL. Among mice injected with DNA-encoded monoclonal antibodies, 75%–77% were protected against an acute challenge by Borrelia-infected ticks. Our results represent the first demonstration of employing DNA transfer as a delivery system for antibodies that block transmission of Borrelia in animal models.

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Babcock, Gregory J., Teresa J. Broering, Hector J. Hernandez, Robert B. Mandell, Katherine Donahue, Naomi Boatright, Anne M. Stack, et al. "Human Monoclonal Antibodies Directed against Toxins A and B Prevent Clostridium difficile-Induced Mortality in Hamsters." Infection and Immunity 74, no. 11 (September 11, 2006): 6339–47. http://dx.doi.org/10.1128/iai.00982-06.

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ABSTRACT Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin A or toxin B in cell-based in vitro neutralization assays. Three anti-toxin A HuMAbs (3H2, CDA1, and 1B11) could all inhibit the enterotoxicity of toxin A in mouse intestinal loops and the in vivo toxicity in a systemic mouse model. Four anti-toxin B HuMAbs (MDX-1388, 103-174, 1G10, and 2A11) could neutralize cytotoxicity in vitro, although systemic toxicity in the mouse could not be neutralized. Anti-toxin A HuMAb CDA1 and anti-toxin B HuMAb MDX-1388 were tested in the well-established hamster model of C. difficile disease. CDA1 alone resulted in a statistically significant reduction of mortality in hamsters; however, the combination treatment offered enhanced protection. Compared to controls, combination therapy reduced mortality from 100% to 45% (P < 0.0001) in the primary disease hamster model and from 78% to 32% (P < 0.0001) in the less stringent relapse model.

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Matsumura, Takuhiro, Sho Amatsu, Ryo Misaki, Masahiro Yutani, Anariwa Du, Tomoko Kohda, Kazuhito Fujiyama, Kazuyoshi Ikuta, and Yukako Fujinaga. "Fully Human Monoclonal Antibodies Effectively Neutralizing Botulinum Neurotoxin Serotype B." Toxins 12, no. 5 (May 7, 2020): 302. http://dx.doi.org/10.3390/toxins12050302.

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Botulinum neurotoxin (BoNT) is the most potent natural toxin known. Of the seven BoNT serotypes (A to G), types A, B, E, and F cause human botulism. Treatment of human botulism requires the development of effective toxin-neutralizing antibodies without side effects such as serum sickness and anaphylaxis. In this study, we generated fully human monoclonal antibodies (HuMAbs) against serotype B BoNT (BoNT/B1) using a murine–human chimera fusion partner cell line named SPYMEG. Of these HuMAbs, M2, which specifically binds to the light chain of BoNT/B1, showed neutralization activity in a mouse bioassay (approximately 10 i.p. LD50/100 µg of antibody), and M4, which binds to the C-terminal of heavy chain, showed partial protection. The combination of two HuMAbs, M2 (1.25 µg) and M4 (1.25 µg), was able to completely neutralize BoNT/B1 (80 i.p. LD50) with a potency greater than 80 i.p. LD50/2.5 µg of antibodies, and was effective both prophylactically and therapeutically in the mouse model of botulism. Moreover, this combination showed broad neutralization activity against three type B subtypes, namely BoNT/B1, BoNT/B2, and BoNT/B6. These data demonstrate that the combination of M2 and M4 is promising in terms of a foundation for new human therapeutics for BoNT/B intoxication.

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Eren, Rachel, Dorit Landstein, Dov Terkieltaub, Ofer Nussbaum, Arie Zauberman, Judith Ben-Porath, Judith Gopher, et al. "Preclinical Evaluation of Two Neutralizing Human Monoclonal Antibodies against Hepatitis C Virus (HCV): a Potential Treatment To Prevent HCV Reinfection in Liver Transplant Patients." Journal of Virology 80, no. 6 (March 15, 2006): 2654–64. http://dx.doi.org/10.1128/jvi.80.6.2654-2664.2006.

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ABSTRACT Passive immunotherapy is potentially effective in preventing reinfection of liver grafts in hepatitis C virus (HCV)-associated liver transplant patients. A combination of monoclonal antibodies directed against different epitopes may be advantageous against a highly mutating virus such as HCV. Two human monoclonal antibodies (HumAbs) against the E2 envelope protein of HCV were developed and tested for the ability to neutralize the virus and prevent human liver infection. These antibodies, designated HCV-AB 68 and HCV-AB 65, recognize different conformational epitopes on E2. They were characterized in vitro biochemically and functionally. Both HumAbs are immunoglobulin G1 and have affinity constants to recombinant E2 constructs in the range of 10−10 M. They are able to immunoprecipitate HCV particles from infected patients' sera from diverse genotypes and to stain HCV-infected human liver tissue. Both antibodies can fix complement and form immune complexes, but they do not activate complement-dependent or antibody-dependent cytotoxicity. Upon complement fixation, the monoclonal antibodies induce phagocytosis of the immune complexes by neutrophils, suggesting that the mechanism of viral clearance includes endocytosis. In vivo, in the HCV-Trimera model, both HumAbs were capable of inhibiting HCV infection of human liver fragments and of reducing the mean viral load in HCV-positive animals. The demonstrated neutralizing activities of HCV-AB 68 and HCV-AB 65 suggest that they have the potential to prevent reinfection in liver transplant patients and to serve as prophylactic treatment in postexposure events.

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Sootichote, Rochanawan, Wilarat Puangmanee, Surachet Benjathummarak, Siriporn Kowaboot, Atsushi Yamanaka, Korbporn Boonnak, Sumate Ampawong, Supawat Chatchen, Pongrama Ramasoota, and Pannamthip Pitaksajjakul. "Potential Protective Effect of Dengue NS1 Human Monoclonal Antibodies against Dengue and Zika Virus Infections." Biomedicines 11, no. 1 (January 16, 2023): 227. http://dx.doi.org/10.3390/biomedicines11010227.

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Due to the lack of an effective therapeutic treatment to flavivirus, dengue virus (DENV) nonstructural protein 1 (NS1) has been considered to develop a vaccine owing to its lack of a role in antibody-dependent enhancement (ADE). However, both NS1 and its antibody have shown cross-reactivity to host molecules and have stimulated anti-DENV NS1 antibody-mediated endothelial damage and platelet dysfunction. To overcome the pathogenic events and reactogenicity, human monoclonal antibodies (HuMAbs) against DENV NS1 were generated from DENV-infected patients. Herein, the four DENV NS1-specific HuMAbs revealed the therapeutic effects in viral neutralization, reduction of viral replication, and enhancement of cell cytolysis of DENV and zika virus (ZIKV) via complement pathway. Furthermore, we demonstrate that DENV and ZIKV NS1 trigger endothelial dysfunction, leading to vascular permeability in vitro. Nevertheless, the pathogenic effects from NS1 were impeded by 2 HuMAbs (D25-4D4C3 and D25-2B11E7) and also protected the massive cytokines stimulation (interleukin [IL-]-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-13, IL-17, eotaxin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1 α, MIP-1β, tumor necrosis factor-α, platelet-derived growth factor, and RANTES). Collectively, our findings suggest that the novel protective NS1 monoclonal antibodies generated from humans has multiple therapeutic benefits against DENV and ZIKV infections.

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Sheppard, Neil C., Sarah L. Davies, Simon A. Jeffs, Sueli M. Vieira, and Quentin J. Sattentau. "Production and Characterization of High-Affinity Human Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Envelope Glycoproteins in a Mouse Model Expressing Human Immunoglobulins." Clinical and Vaccine Immunology 14, no. 2 (December 13, 2006): 157–67. http://dx.doi.org/10.1128/cvi.00274-06.

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ABSTRACT Human (Hu) monoclonal antibodies (MAbs) against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) are useful tools in the structural and functional analysis of Env, are under development both as potential prophylaxis and as therapy for established HIV-1 infection, and have crucial roles in guiding the design of preventative vaccines. Despite representing more than 50% of infections globally, no MAbs have been generated in any species against C clade HIV-1 Env. To generate HuMAbs to a novel Chinese C clade Env vaccine candidate (primary isolate strain HIV-197CN54), we used BAB5 mice that express a human immunoglobulin (Ig) M antibody repertoire in place of endogenous murine immunoglobulins. When immunized with HIV-197CN54 Env, these mice developed antigen-specific IgM antibodies. Hybridoma fusions using splenocytes from these mice enabled the isolation of two Env-specific IgM HuMAbs: N3C5 and N03B11. N3C5 bound to HIV-1 Env from clades A and C, whereas N03B11 bound two geographically distant clade C isolates but not Env from other clades. These HuMAbs bind conformational epitopes within the immunodominant region of the gp41 ectodomain. N3C5 weakly neutralized the autologous isolate in the absence of complement and weakly enhanced infection in the presence of complement. N03B11 has no effect on infectivity in either the presence or the absence of complement. These novel HuMAbs are useful reagents for the study of HIV-1 Env relevant to the global pandemic, and mice producing human immunoglobulin present a tool for the production of such antibodies.

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Sheoran, Abhineet S., Susan Chapman, Pradeep Singh, Arthur Donohue-Rolfe, and Saul Tzipori. "Stx2-Specific Human Monoclonal Antibodies Protect Mice against Lethal Infection with Escherichia coli Expressing Stx2 Variants." Infection and Immunity 71, no. 6 (June 2003): 3125–30. http://dx.doi.org/10.1128/iai.71.6.3125-3130.2003.

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ABSTRACT Shiga toxin-producing Escherichia coli (STEC) strains are responsible for causing hemolytic-uremic syndrome (HUS), and systemic administration of Shiga toxin (Stx)-specific human monoclonal antibodies (HuMAbs) is considered a promising approach for prevention or treatment of the disease in children. The goal of the present study was to investigate the ability of Stx2-specific HuMAbs to protect against infections with STEC strains that produce Stx2 variants. Dose-response studies on five HuMAbs, using the mouse toxicity model, revealed that only the three directed against the A subunit were protective against Stx2 variants, and 5C12 was the most effective among the three tested. Two HuMAbs directed against the B subunit, while highly effective against Stx2, were ineffective against Stx2 variants. In a streptomycin-treated mouse model, parenteral administration of 5C12 significantly protected mice up to 48 h after oral bacterial challenge. We conclude that 5C12, reactive against the Stx2 A subunit, is an excellent candidate for immunotherapy against HUS and that antibodies directed against the A subunit of Stx2 have broad-spectrum activity that includes Stx2 variants, compared with those directed against the B subunit.

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Krautz-Peterson, Greice, Susan Chapman-Bonofiglio, Karen Boisvert, Hanping Feng, Ira M. Herman, Saul Tzipori, and Abhineet S. Sheoran. "Intracellular Neutralization of Shiga Toxin 2 by an A Subunit-Specific Human Monoclonal Antibody." Infection and Immunity 76, no. 5 (February 19, 2008): 1931–39. http://dx.doi.org/10.1128/iai.01282-07.

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ABSTRACT Infection of children with Shiga toxin (Stx)-producing Escherichia coli (STEC) is the leading cause of hemolytic-uremic syndrome (HUS). Stx2, one of two toxins liberated by the bacteria, is directly linked with HUS. We have previously shown that Stx2-specific human monoclonal antibodies (HuMAbs) protect mice and piglets from fatal systemic complications of Stx2. The present study investigates the mechanisms by which our most efficacious A- and B-subunit-specific HuMAbs neutralize the cytotoxic effects of Stx2 in vitro. Whereas the B-subunit-specific HuMAb 5H8 blocked binding of Stx2 to its receptor on the cell surface, the A-subunit-specific HuMAb 5C12 did not interfere with the toxin-receptor binding. Further investigations revealed that 5C12 did not block endocytosis of Stx2 by HeLa cells as both Stx2 and 5C12 colocalized with early endosomes. However, 5C12 blocked the retrograde transport of the toxin into the Golgi and the endoplasmic reticulum, preventing the toxin from entering the cytosol where the toxin exerts its cytotoxic effect. The endocytosed 5C12/Stx2 complexes appear to be rapidly transported to the plasma membrane and/or to the slow recycling perinuclear compartments, followed by their slow recycling to the plasma membrane, and release into the extracellular environment.

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Akiyoshi, D. E., C. M. Rich, S. O'Sullivan-Murphy, L. Richard, J. Dilo, A. Donohue-Rolfe, A. S. Sheoran, S. Chapman-Bonofiglio, and S. Tzipori. "Characterization of a Human Monoclonal Antibody against Shiga Toxin 2 Expressed in Chinese Hamster Ovary Cells." Infection and Immunity 73, no. 7 (July 2005): 4054–61. http://dx.doi.org/10.1128/iai.73.7.4054-4061.2005.

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ABSTRACT Shiga toxin-producing Escherichia coli infections can often lead to the development of hemolytic-uremic syndrome (HUS) in a small percentage of infected humans. Patients with HUS receive only supportive treatment as the benefit of antibiotic therapy remains uncertain. We have previously reported the generation and preclinical evaluation of neutralizing human monoclonal antibodies (HuMAbs) against the Shiga toxins (Stx). In this paper, we describe the expression in Chinese hamster ovary (CHO) cells of 5C12 HuMAb, which is directed against the A subunit of Stx2. The cDNAs of the light and heavy chain immunoglobulin (Ig) variable regions of 5C12 HuMAb were isolated and cloned into an expression vector containing human IgG1 constant regions. The vector was transfected into CHO cells, and transfectants secreting Stx2-specific antibody were screened by an Stx2-specific enzyme-linked immunosorbent assay. The CHO-produced recombinant 5C12 (r5C12) showed similar specificity and binding affinity to Stx2 as the parent hybridoma-produced 5C12. More significantly, the r5C12 displayed the same neutralizing activity as the parent 5C12 in vitro and in vivo. In the mouse toxicity model, both antibodies significantly and equally prolonged survival at a dose of 0.312 μg/mouse. The data showed that since r5C12, produced in CHO cells, was equally effective as the parent 5C12, it is our choice candidate as a potential prophylactic or therapeutic agent against hemolytic-uremic syndrome.

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Sutkowski, Natalie, Wei Sun, and Daniel Fernandes. "Antibody immunotherapy targeting the self-tumor antigen nucleolin (VAC5P.1129)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 73.14. http://dx.doi.org/10.4049/jimmunol.194.supp.73.14.

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Abstract Nucleolin is a multifunctional protein found in the nucleus of all cells, and it’s a self-tumor antigen. It is overexpressed on the plasma membrane and cytoplasm of the two most common forms of leukemia acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). The cell surface expression of nucleolin on CLL and AML cells, compared with its nuclear profile in normal cells, makes nucleolin an attractive self-antigenic target for antibody immunotherapy. Accordingly, we have utilized our patented platform technology (US Patent 8,715,743) to generate a panel of fully human monoclonal antibodies (HuMAbs) that target nucleolin (NCL) and potently induce AML cell death, while having no effect on normal blood cells (PCT/US2010/057046). Preliminary data indicated that AML cells were killed independently of complement or antibody dependent cellular cytotoxic mechanisms, possibly by interfering with nucleolin’s cellular function. This might have significant therapeutic implications, since the HuMAbs may retain activity in immunocompromised leukemia patients. We hypothesize that the anti-NCL HuMAbs have both immune mediated and immune independent antitumor activity, eliciting nucleolin specific killing through both complement and cell mediated cytotoxic mechanisms, and through interfering with the integral cellular function of nucleolin. Thus, autoreactive antibodies targeting this self-tumor antigen might be important in the treatment of leukemia.

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14

Sheoran, Abhineet S., Xiaochuan Feng, Inderpal Singh, Susan Chapman-Bonofiglio, Sabrina Kitaka, Joel Hanawalt, John Nunnari, Keith Mansfield, James K. Tumwine, and Saul Tzipori. "Monoclonal Antibodies against Enterocytozoon bieneusi of Human Origin." Clinical Diagnostic Laboratory Immunology 12, no. 9 (September 2005): 1109–13. http://dx.doi.org/10.1128/cdli.12.9.1109-1113.2005.

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ABSTRACT Enterocytozoon bieneusi is clinically the most significant among the microsporidia infecting humans, causing chronic diarrhea, wasting, and cholangitis in individuals with human immunodeficiency virus/AIDS. The lack of immune reagents is largely due to the absence of methods for laboratory propagation of E. bieneusi. We recently described a procedure for the concentration and purification of spores from diarrheic stool of infected humans. Purified spores were used to immunize mice for production and screening of monoclonal antibodies (MAbs) against E. bieneusi. The eight immunoglobulin M MAbs generated and fully characterized did not cross-react with other human microsporidia or with other microorganisms normally present in stool. One of the MAbs, 2G4, reacted with E. bieneusi spores in stools from monkeys and humans, without background fluorescence, which makes it an ideal diagnostic reagent. It also recognizes intracellular stages of the parasite and will be suitable for determining tissue distribution of E. bieneusi in infected hosts. At least two immunodominant antigens of E. bieneusi of 33,000 and 35,000 Da exist, which were recognized by rabbit and mouse antisera. The availability of MAbs against E. bieneusi will simplify considerably the diagnosis of this infection in humans and will provide tools for epidemiologic investigations regarding the true prevalence of the infection in various human and mammalian populations and the environmental sources of infection.

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Ehrlich, P. H., Z. A. Moustafa, J. C. Justice, K. E. Harfeldt, I. K. Gadi, L. J. Sciorra, F. P. Uhl, C. Isaacson, and L. Ostberg. "Human and primate monoclonal antibodies for in vivo therapy." Clinical Chemistry 34, no. 9 (September 1, 1988): 1681–88. http://dx.doi.org/10.1093/clinchem/34.9.1681.

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Abstract Human monoclonal antibodies, owing to their decreased immunogenicity, are expected to be an improvement over mouse monoclonal antibodies for in vivo therapy. Human and primate monoclonal antibodies are best produced with a human x mouse heteromyeloma. Several human chromosomes are stable in the human x (human x mouse) hybrids. Chimpanzee anti-digoxin monoclonal antibodies were prepared and characterized. Because they are structurally very similar to human antibodies, they should be well tolerated in humans. The anti-digoxin antibodies can be used for therapy of extreme overdoses or as an in vivo diagnostic tool for slight overdoses. Because the advantage of using human monoclonal antibodies is their lack of immunogenicity, preparation of the antibody must be scrupulous so as not to introduce extraneous immunogens. Analysis to ensure the purity of the preparation can be complicated by the presence of high concentrations of the antibody and the low levels of contamination that must be detected. We describe a Western blot assay for Protein A that is sensitive even in the presence of human IgG.

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Uchigata, Y., B. S. Prabhakar, K. F. Salata, F. Ginsberg-Fellner, and A. L. Notkins. "Human monoclonal multiple-organ-reactive autoantibodies distinguished by mouse monoclonal anti-idiotypic antibodies: expression of idiotopes in humans with and without autoimmune diseases." Journal of Immunology 138, no. 12 (June 15, 1987): 4218–21. http://dx.doi.org/10.4049/jimmunol.138.12.4218.

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Abstract Previously we reported on the production and characteristics of a number of human monoclonal autoantibodies. All of these autoantibodies were of the IgM class and reacted with antigens in multiple organs. In this study we generated IgG murine monoclonal anti-idiotypic antibodies against five human monoclonal autoantibodies, (i.e., MOR-h2, MOR-h3, MOR-h4, CG1, and CG2). These anti-idiotypic antibodies reacted strongly with the corresponding human monoclonal autoantibody, but minimally or not at all with other human monoclonal autoantibodies. By using these anti-idiotypic antibodies as probes, we screened sera obtained from normal individuals and patients with insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, and systemic lupus erythematosus for the expression of idiotopes. Our study showed that the idiotopes recognized by three of the anti-idiotypic antibodies, i.e., anti-CG1, anti-CG2, and anti-MOR-h2, were not expressed, but the idiotopes recognized by two of the anti-idiotypic antibodies, i.e., anti-MOR-h3 and anti-MOR-h4, were expressed in normal individuals. In patients with autoimmune disorders, there was no increase in the expression of the CG1, CG2, and MOR-h2 idiotopes, but 45 and 23% of the patients with systemic lupus erythematosus showed a significant increase in the expression of the MOR-h3 and MOR-h4 idiotopes respectively. These findings show that there is widespread expression in the B cell repertoire of certain autoantibody-associated idiotopes.

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Shawler, D. L., R. M. Bartholomew, L. M. Smith, and R. O. Dillman. "Human immune response to multiple injections of murine monoclonal IgG." Journal of Immunology 135, no. 2 (August 1, 1985): 1530–35. http://dx.doi.org/10.4049/jimmunol.135.2.1530.

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Abstract Murine monoclonal antibody infusions in humans should induce a human anti-mouse immunoglobulin (mIgG) immune response, especially if multiple infusions over an extended period of time are necessary for therapeutic efficacy. We have administered multiple infusions of the murine monoclonal antibody T101 to patients with cutaneous T cell lymphoma (CTCL) or chronic lymphocytic leukemia (CLL). Five of 10 CTCL patients, compared with zero of six CLL patients, developed antibodies to mIgG. In those CTCL patients who did not demonstrate anti-mIgG antibodies, we were unable to correlate the lack of response to any of a large number of clinical parameters. Anti-mIgG antibodies were of both the mu and gamma isotypes and were detectable 14 days after the first infusion. Multiple infusions were associated with elevated titers. The anti-idiotypic portion of the anti-mIgG titer steadily increased with each infusion until eventually, in one patient receiving eight weekly infusions, well over one-half the serum anti-mIgG recognized only T101 and not four other murine IgG2AK antibodies tested. To increase our confidence in these findings, four separate assay systems were used to make these determinations. The identification of anti-idiotype antibodies as the dominant species of the immune response to multiple infusions of murine monoclonal antibody has major implications for future work with monoclonal antibodies. Although it has been suggested that human monoclonal antibodies would obviate an immune response, our work implies that such antibodies might still induce anti-idiotype antibodies if multiple infusions are administered.

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Ball, William J., Rama Kasturi, Purabi Dey, Michael Tabet, Susan O’Donnell, Debra Hudson, and Dianne Fishwild. "Isolation and Characterization of Human Monoclonal Antibodies to Digoxin." Journal of Immunology 163, no. 4 (August 15, 1999): 2291–98. http://dx.doi.org/10.4049/jimmunol.163.4.2291.

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Abstract Fab preparations of sheep polyclonal anti-digoxin Abs have proven useful for reversal of the toxic effects of digoxin overdoses in patients. Unfortunately, the use of foreign species proteins in humans is limited because of the potential for immunological responses that include hypersensitivity reactions and acute anaphylaxis. Immunization of recently developed transgenic mice, whose endogenous μ heavy and κ light chain Ig genes are inactivated and which carry human Ig gene segments, with a digoxin-protein conjugate has enabled us to generate and isolate eight hybridoma cell lines secreting human sequence anti-digoxin mAbs. Six of the mAbs have been partially characterized and shown to have high specificity and low nanomolar affinities for digoxin. In addition, detailed competition binding studies performed with three of these mAbs have shown them to have distinct differences in their digoxin binding, and that all three structural moieties of the drug, the primary digitoxose sugar, steroid, and five-member unsaturated lactone ring, contribute to Ab recognition.

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Magnani, Diogo M., Thomas F. Rogers, Nathan Beutler, Michael J. Ricciardi, Varian K. Bailey, Lucas Gonzalez-Nieto, Bryan Briney, et al. "Neutralizing human monoclonal antibodies prevent Zika virus infection in macaques." Science Translational Medicine 9, no. 410 (October 4, 2017): eaan8184. http://dx.doi.org/10.1126/scitranslmed.aan8184.

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Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies (nmAbs) from the plasmablasts of a ZIKV-infected patient—SMZAb1, SMZAb2, and SMZAb5—directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fcγ receptor binding, thus eliminating potential therapy-mediated antibody-dependent enhancement. We administered a cocktail of these three nmAbs to nonhuman primates 1 day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum after challenge. Given that numerous antibodies have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses.

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Jin, Jing, and Graham Simmons. "Antiviral Functions of Monoclonal Antibodies against Chikungunya Virus." Viruses 11, no. 4 (March 28, 2019): 305. http://dx.doi.org/10.3390/v11040305.

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Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide. Antibodies play pivotal roles in the immune response to infection. Increasingly, therapeutic antibodies are becoming important for protection from pathogen infection for which neither vaccine nor treatment is available, such as CHIKV infection. The new generation of ultra-potent and/or broadly cross-reactive monoclonal antibodies (mAbs) provides new opportunities for intervention. In the past decade, several potent human and mouse anti-CHIKV mAbs were isolated and demonstrated to be protective in vivo. Mechanistic studies of these mAbs suggest that mAbs exert multiple modes of action cooperatively. Better understanding of these antiviral mechanisms for mAbs will help to optimize mAb therapies.

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Zeng, L., M. Takeya, X. Ling, A. Nagasaki, and K. Takahashi. "Interspecies reactivities of anti-human macrophage monoclonal antibodies to various animal species." Journal of Histochemistry & Cytochemistry 44, no. 8 (August 1996): 845–53. http://dx.doi.org/10.1177/44.8.8756757.

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We examined interspecies reactivities of eight anti-human monocyte/macrophage monoclonal antibodies (MAbs), Am-3K, PM-2K, X4, X14, Ber-MAC3, GHI/61, EBM/11, and KP1, with various animal tissues including rats, guinea pigs, rabbits, cats, dogs, goats, pigs, bovines, horses, and monkeys. All MAbs recognized monkey macrophages. Pig macrophages were detected by most MAbs except for EBM/11 and KP1. Of the eight antibodies, AM-3K showed the widest interspecies reactivity. It reacted with macrophages of all animal species examined, except for rats. Western blot analysis revealed a similarity in the antigens recognized by AM-3K among guinea pigs, rabbits, and humans. Other anti-human MAbs demonstrated distinct reactive patterns against macrophages in animals. The immunostaining patterns of all of these MAbs in animal tissues were similar to those found in humans, although some MAbs, such as AM-3K, EBM/11, and X4, displayed more restricted reactivity in animals than in humans. These results indicate that some anti-human monocyte/macrophage MAbs are also available for immunohistochemical detection of monocyte/macrophages in animal tissues. Among them, AM-3K is considered to be the most useful MAb for identifying macrophages in various tissues of animals.

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Skinner, Benjamin, Sierra Mikula, Brent S. Davis, Jordan A. Powers, Holly R. Hughes, and Amanda E. Calvert. "Monoclonal antibodies to Cache Valley virus for serological diagnosis." PLOS Neglected Tropical Diseases 16, no. 1 (January 24, 2022): e0010156. http://dx.doi.org/10.1371/journal.pntd.0010156.

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Cache Valley virus (CVV) is a mosquito-borne virus in the genus Orthobunyavirus, family Peribunyaviridae. It was first isolated from a Culiseta inorata mosquito in Cache Valley, Utah in 1956 and is known to circulate widely in the Americas. While only a handful of human cases have been reported since its discovery, it is the causative agent of fetal death and severe malformations in livestock. CVV has recently emerged as a potential viral pathogen causing severe disease in humans. Currently, the only serological assay available for diagnostic testing is plaque reduction neutralization test which takes several days to perform and requires biocontainment. To expand diagnostic capacity to detect CVV infections by immunoassays, 12 hybridoma clones secreting anti-CVV murine monoclonal antibodies (MAbs) were developed. All MAbs developed were found to be non-neutralizing and specific to the nucleoprotein of CVV. Cross-reactivity experiments with related orthobunyaviruses revealed several of the MAbs reacted with Tensaw, Fort Sherman, Tlacotalpan, Maguari, Playas, and Potosi viruses. Our data shows that MAbs CVV14, CVV15, CVV17, and CVV18 have high specific reactivity as a detector in an IgM antibody capture test with human sera.

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May, Kenneth F., Sameek Roychowdhury, Darshna Bhatt, Ergun Kocak, Xue-Feng Bai, Jin-Qing Liu, Amy K. Ferketich, et al. "Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies." Blood 105, no. 3 (February 1, 2005): 1114–20. http://dx.doi.org/10.1182/blood-2004-07-2561.

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AbstractWhen adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a “translation” fails because of an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is, therefore, desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti–mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T-cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of Epstein-Barr virus (EBV)–associated lymphoma development to screen a panel of anti–human CTLA-4 monoclonal antibodies (mAbs) for their effect on human lymphocytes in an in vivo “humanized” environment. We report significant heterogeneity of anti–human CTLA-4 mAbs in enhancing the expansion of human T cells in mice, and this heterogeneity cannot be attributed to immunoglobulin isotypes or affinity for CTLA-4. These data validate the development of additional screening tools, such as the one described, to further characterize functional activity of antihuman antibodies before proceeding with clinical translation to human studies.

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Jia, Manxue, Hong Lu, Martin Markowitz, Cecilia Cheng-Mayer, and Xueling Wu. "Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIVSF162P3N-Infected Macaques." Journal of Virology 90, no. 8 (February 3, 2016): 4017–31. http://dx.doi.org/10.1128/jvi.02898-15.

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ABSTRACTTo improve our understanding of the similarities and differences between neutralizing antibodies elicited by simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and human immunodeficiency virus type 1 (HIV-1)-infected humans, we examined the plasma of 13 viremic macaques infected with SHIVSF162P3Nand 85 HIV-1-infected humans with known times of infection. We identified 5 macaques (38%) from 1 to 2 years postinfection (p.i.) with broadly neutralizing antibodies (bnAbs) against tier 2 HIV-1. In comparison, only 2 out of 42 (5%) human plasma samples collected in a similar time frame of 1 to 3 years p.i. exhibited comparable neutralizing breadths and potencies, with the number increasing to 7 out of 21 (30%) after 3 years p.i. Plasma mapping with monomeric gp120 identified only 2 out of 9 humans and 2 out of 4 macaques that contained gp120-reactive neutralizing antibodies, indicating distinct specificities in these plasma samples, with most of them recognizing the envelope trimer (including gp41) rather than the gp120 monomer. Indeed, a total of 20 gp120-directed monoclonal antibodies (MAbs) isolated from a human subject (AD358) and a Chinese rhesus macaque (GB40) displayed no or limited neutralizing activity against tier 2 strains. These isolated MAbs, mapped to the CD4-binding site, the V3 loop, the inner domain, and the C5 region of gp120, revealed genetic similarity between the human and macaque immunoglobulin genes used to encode some V3-directed MAbs. These results also support the use of envelope trimer probes for efficient isolation of HIV-1 bnAbs.IMPORTANCEHIV-1 vaccine research can benefit from understanding the development of broadly neutralizing antibodies (bnAbs) in rhesus macaques, commonly used to assess vaccine immunogenicity and efficacy. Here, we examined 85 HIV-1-infected humans and 13 SHIVSF162P3N-infected macaques for bnAbs and found that, similar to HIV-1-infected humans, bnAbs in SHIV-infected macaques are also rare, but their development might have been faster in some of the studied macaques. Plasma mapping with monomeric gp120 indicated that most bnAbs bind to the envelope trimer rather than the gp120 monomer. In support of this, none of the isolated gp120-reactive monoclonal antibodies (MAbs) displayed the neutralization breadth observed in the corresponding plasma. However, the MAb sequences revealed similarity between human and macaque genes used to encode some V3-directed MAbs. Our study sheds light on the timing and development of bnAbs in SHIV-infected macaques in comparison to HIV-1-infected humans and highlights the use of envelope trimer probes for efficient recovery of bnAbs.

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Olsen, Ole, Steve Frey, Christy Boozer, Glen Grandea, Mike Cicarelli, Rebecca Lily, Courtney Ward, et al. "A strategy to identify human monoclonal antibodies that neutralize a broad spectrum of influenza A subtypes (38.12)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 38.12. http://dx.doi.org/10.4049/jimmunol.184.supp.38.12.

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Abstract Influenza A continues to be a serious public health threat as it continuously evolves to evade and escape immune surveillance through genetic drift, shift, and re-assortment. Hemagglutinin (HA) is the main glycoprotein target of the humoral immune response and elicits protective, neutralizing, antibodies during infection. However, these antibodies are usually specific for the influenza subtype causing infection and exhibit a narrow spectrum of protectiveness. To date, many of the influenza-neutralizing monoclonal antibodies described are cross-specific for subtypes H1 and H5 but do not neutralize subtypes H3 or H7. Therefore, we have designed an approach to survey the human B cell repertoire to identify monoclonal antibodies that neutralize influenza viruses of both the H1 and H3 subtypes. Our strategy is to identify humans that have broadly reactive serum antibodies, culture IgG+ memory B cells from these individuals at near clonal density, and then assay the culture supernatants for the presence of antibodies that neutralize both H1 and H3 influenza subtypes. By combining functional and binding assays we will determine if there exist in nature highly conserved neutralizing epitopes that are represented on most or all of the influenza HA subtypes tested.

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Khalili-Shirazi, Azadeh, Linda Summers, Jacqueline Linehan, Gary Mallinson, David Anstee, Simon Hawke, Graham S. Jackson, and John Collinge. "PrP glycoforms are associated in a strain-specific ratio in native PrPSc." Journal of General Virology 86, no. 9 (September 1, 2005): 2635–44. http://dx.doi.org/10.1099/vir.0.80375-0.

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Prion diseases involve conversion of host-encoded cellular prion protein (PrPC) to a disease-related isoform (PrPSc). Using recombinant human β-PrP, a panel of monoclonal antibodies was produced that efficiently immunoprecipitated native PrPSc and recognized epitopes between residues 93–105, indicating for the first time that this region is exposed in both human vCJD and mouse RML prions. In contrast, monoclonal antibodies raised to human α-PrP were more efficient in immunoprecipitating PrPC than PrPSc, and some of them could also distinguish between different PrP glycoforms. Using these monoclonal antibodies, the physical association of PrP glycoforms was studied in normal brain and in the brains of humans and mice with prion disease. It was shown that while PrPC glycoforms can be selectively immunoprecipitated, the differentially glycosylated molecules of native PrPSc are closely associated and always immunoprecipitate together. Furthermore, the ratio of glycoforms comprising immunoprecipitated native PrPSc from diverse prion strains was similar to those observed on denaturing Western blots. These studies are consistent with the view that the proportion of each glycoform incorporated into PrPSc is probably controlled in a strain-specific manner and that each PrPSc particle contains a mixture of glycoforms.

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Ying, Tianlei, Lanying Du, Tina W. Ju, Ponraj Prabakaran, Candy C. Y. Lau, Lu Lu, Qi Liu, et al. "Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies." Journal of Virology 88, no. 14 (April 30, 2014): 7796–805. http://dx.doi.org/10.1128/jvi.00912-14.

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ABSTRACTThe recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naïve-antibody library (containing ∼1011antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 μg/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses.IMPORTANCEA novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV.

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Ziegler, A., T. Hirsch, W. Krause, K. Neumann, G. Schieferstein, G. Dohr, S. Kohlstädt, and B. Uchanska-Ziegler. "Monoclonal antibodies against antigens expressed by human sperm: Monoklonale Antikörper mit Spezifität für humane Spermatozoenantigene." Andrologia 22, S1 (April 27, 2009): 101–9. http://dx.doi.org/10.1111/j.1439-0272.1990.tb02076.x.

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Selvaraj, S., M. R. Suresh, G. McLean, D. Willans, C. Turner, D. M. Haines, M. Longenecker, and A. Noujaim. "A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors." Nuklearmedizin 26, no. 01 (1987): 1–6. http://dx.doi.org/10.1055/s-0038-1624353.

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The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

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Malonis, Ryan J., James T. Earnest, Arthur S. Kim, Matthew Angeliadis, Frederick W. Holtsberg, M. Javad Aman, Rohit K. Jangra, et al. "Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses." Proceedings of the National Academy of Sciences 118, no. 37 (September 10, 2021): e2100104118. http://dx.doi.org/10.1073/pnas.2100104118.

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Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline–revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections.

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Madani, Navid, Amy M. Princiotto, David Easterhoff, Todd Bradley, Kan Luo, Wilton B. Williams, Hua-Xin Liao, et al. "Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds." Journal of Virology 90, no. 10 (March 9, 2016): 5031–46. http://dx.doi.org/10.1128/jvi.03211-15.

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ABSTRACTThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

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Thornton, Christopher R. "Tracking the Emerging Human Pathogen Pseudallescheria boydii by Using Highly Specific Monoclonal Antibodies." Clinical and Vaccine Immunology 16, no. 5 (March 25, 2009): 756–64. http://dx.doi.org/10.1128/cvi.00061-09.

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ABSTRACT Pseudallescheria boydii has long been known to cause white grain mycetoma in immunocompetent humans, but it has recently emerged as an opportunistic pathogen of humans, causing potentially fatal invasive infections in immunocompromised individuals and evacuees of natural disasters, such as tsunamis and hurricanes. The diagnosis of P. boydii is problematic since it exhibits morphological characteristics similar to those of other hyaline fungi that cause infectious diseases, such as Aspergillus fumigatus and Scedosporium prolificans. This paper describes the development of immunoglobulin M (IgM) and IgG1 κ-light chain monoclonal antibodies (MAbs) specific to P. boydii and certain closely related fungi. The MAbs bind to an immunodominant carbohydrate epitope on an extracellular 120-kDa antigen present in the spore and hyphal cell walls of P. boydii and Scedosporium apiospermum. The MAbs do not react with S. prolificans, Scedosporium dehoogii, or a large number of clinically relevant fungi, including A. fumigatus, Candida albicans, Cryptococcus neoformans, Fusarium solani, and Rhizopus oryzae. The MAbs were used in immunofluorescence and double-antibody sandwich enzyme-linked immunosorbent assays (DAS-ELISAs) to accurately differentiate P. boydii from other infectious fungi and to track the pathogen in environmental samples. Specificity of the DAS-ELISA was confirmed by sequencing of the internally transcribed spacer 1 (ITS1)-5.8S-ITS2 rRNA-encoding regions of environmental isolates.

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Smet, Anouk, Joao Paulo Portela Catani, Tine Ysenbaert, Amanda Gonçalves, Harry Kleanthous, Thorsten U. Vogel, Xavier Saelens, and Emma R. Job. "Antibodies directed towards neuraminidase restrict influenza virus replication in primary human bronchial epithelial cells." PLOS ONE 17, no. 1 (January 31, 2022): e0262873. http://dx.doi.org/10.1371/journal.pone.0262873.

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Influenza neuraminidase (NA) is implicated in various aspects of the virus replication cycle and therefore is an attractive target for vaccination and antiviral strategies. Here we investigated the potential for NA-specific antibodies to interfere with A(H1N1)pdm09 replication in primary human airway epithelial (HAE) cells. Mouse polyclonal anti-NA sera and a monoclonal antibody could block initial viral entry into HAE cells as well as egress from the cell surface. NA-specific polyclonal serum also reduced virus replication across multiple rounds of infection. Restriction of virus entry correlated with the ability of the serum or monoclonal antibody to mediate neuraminidase inhibition (NI). Finally, human sera with NI activity against the N1 of A(H1N1)pdm09 could decrease H6N1 virus infection of HAE cells, highlighting the potential contribution of anti-NA antibodies in the control of influenza virus infection in humans.

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Liu, Chang, Yeon Su Kim, John Hok-Nin Lowe, and Shan Chung. "A cell-based FcRn-dependent recycling assay for predictive pharmacokinetic assessment of therapeutic antibodies." Bioanalysis 13, no. 14 (July 2021): 1135–44. http://dx.doi.org/10.4155/bio-2021-0099.

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Aim: Evaluation of suitable pharmacokinetic properties is critical for successful development of IgG-based biotherapeutics. The prolonged half-lives of IgGs depend on the intracellular trafficking function of neonatal Fc receptor, which rescues internalized IgGs from lysosomal degradation and recycles them back to circulation. Results: Here, we developed a novel cell-based assay to quantify recycling of monoclonal antibodies in a transwell culture system that uses a cell line that stably expresses human neonatal Fc receptor. We tested seven therapeutic antibodies and showed that the recycling output of the assay strongly correlated with the clearance in humans. Conclusion: This recycling assay has potential application as a pharmacokinetic prescreening tool to facilitate development and selection of IgG-based candidate therapeutic monoclonal antibodies.

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Kostense, Stefan, Susan Moore, Arjen Companjen, Alexander B. H. Bakker, Wilfred E. Marissen, Rie von Eyben, Gerrit Jan Weverling, Cathleen Hanlon, and Jaap Goudsmit. "Validation of the Rapid Fluorescent Focus Inhibition Test for Rabies Virus-Neutralizing Antibodies in Clinical Samples." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 30, 2012): 3524–30. http://dx.doi.org/10.1128/aac.06179-11.

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ABSTRACTMonoclonal antibodies are successful biologics in treating a variety of diseases, including the prevention or treatment of viral infections. CL184 is a 1:1 combination of two human monoclonal IgG1 antibodies (CR57 and CR4098) against rabies virus, produced in the PER.C6 human cell line. The two antibodies are developed as replacements of human rabies immune globulin (HRIG) and equine rabies immune globulin (ERIG) in postexposure prophylaxis (PEP). The rapid fluorescent focus inhibition test (RFFIT) is a cell-based virus neutralization assay which is usually performed to determine the biological potency of a vaccine and to measure the levels of protection against rabies in humans and animals. In order to confirm the suitability of this assay as a pharmacodynamic assay, we conducted a validation using both HRIG- and CL184-spiked serum samples and sera from vaccinated donors. The validation results met all analytical acceptance criteria and showed that HRIG and CL184 serum concentrations can be compared. Stability experiments showed that serum samples were stable in various suboptimal conditions but that rabies virus should be handled swiftly once thawed. We concluded that the assay is suitable for the measurement of polyclonal and monoclonal rabies neutralizing antibodies in clinical serum samples.

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Mukherjee, Jean, Kerry Chios, Dianne Fishwild, Deborah Hudson, Susan O'Donnell, Stephen M. Rich, Arthur Donohue-Rolfe, and Saul Tzipori. "Production and Characterization of Protective Human Antibodies against Shiga Toxin 1." Infection and Immunity 70, no. 10 (October 2002): 5896–99. http://dx.doi.org/10.1128/iai.70.10.5896-5899.2002.

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ABSTRACT Hemolytic-uremic syndrome (HUS) is a serious complication which is predominantly associated in children with infection by Shiga toxin-producing Escherichia coli (STEC). By using HuMAb-Mouse (Medarex) animals, human monoclonal antibodies (Hu-MAbs) were developed against Shiga toxin 1 (Stx1) for passive immunotherapy of HUS. Ten stable hybridomas comprised of fully human heavy- and light-chain immunoglobulin elements and secreting Stx1-specific Hu-MAbs (seven immunoglobulin M(κ) [IgM(κ)] elements [one specific for the A subunit and six specific for the B subunit] and three IgG1(κ) elements specific for subunit B) were isolated. Two IgM(κ) Hu-MAbs (2D9 and 15G9) and three IgG1(κ) Hu-MAbs (5A4, 10F4, and 15G2), all specific for subunit B, demonstrated marked neutralization of Stx1 in vitro and significant prolongation of survival in a murine model of Stx1 toxicosis.

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Khadka, Sunada, Long Vien, Paul Leonard, Laura Bover, and Florian Muller. "Generation and Validation of an Anti-Human PANK3 Mouse Monoclonal Antibody." Biomolecules 12, no. 9 (September 19, 2022): 1323. http://dx.doi.org/10.3390/biom12091323.

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Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step—phosphorylation of pantothenic acid—catalyzed by pantothenate kinases (PANK1,2,3 in humans, PANK3 being the most highly expressed). Despite the critical importance of CoA in metabolism, the differential roles of PANK isoforms remain poorly understood. Our investigations of PANK proteins as potential precision oncology collateral lethality targets (PANK1 is co-deleted as part of the PTEN locus in some highly aggressive cancers) were severely hindered by a dearth of commercial antibodies that can reliably detect endogenous PANK3 protein. While we successfully validated commercial antibodies for PANK1 and PANK2 using CRISPR knockout cell lines, we found no commercial antibody that could detect endogenous PANK3. We therefore set out to generate a mouse monoclonal antibody against human PANK3 protein. We demonstrate that a clone (Clone MDA-299-62A) can reliably detect endogenous PANK3 protein in cancer cell lines, with band-specificity confirmed by CRISPR PANK3 knockout and knockdown cell lines. Sub-cellular fractionation shows that PANK3 is overwhelmingly cytosolic and expressed broadly across cancer cell lines. PANK3 monoclonal antibody MDA-299-62A should prove a valuable tool for researchers investigating this understudied family of metabolic enzymes in health and disease.

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Anderson, Deborah J., Joseph A. Politch, Gabriela B. Vaca, Kadryn Kadasia, and Kevin J. Whaley. "Use of Monoclonal Antibodies to Prevent the Sexual Transmission of Human Immunodeficiency Virus Type 1." Current Immunology Reviews 15, no. 1 (April 12, 2019): 123–30. http://dx.doi.org/10.2174/1573395514666180605091240.

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<P>Passive immunization has been used since the late 1800’s to prevent and treat human infectious diseases. Administration of animal immune sera and human immunoglobulin has given way to the use of monoclonal antibodies (mAbs) for passive immunization, and highly potent broadly neutralizing anti-HIV antibodies (bNAbs) are now being considered for HIV therapy and prophylaxis. Recent studies have shown that systemic and topical administration of bNAbs can effectively inhibit HIV/SHIV mucosal transmission in macaques and in humanized mice, and selected bNAbs are currently being tested in clinical trials for safety and efficacy in humans. In this review, we outline strategies for the selection, engineering and manufacture of human bNAbs to prevent the sexual transmission of HIV, describe the proof-of-concept animal studies that have demonstrated mAb-mediated protection against mucosal HIV transmission, and review clinical trials currently underway to test the safety and efficacy of mAb-based HIV prevention in humans.

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Léger, Jocelyne, Jeanine Chevalier, Catherine Larue, Patrick Gautier, Jacques Planchenault, Elisabeth Aumaître, Patrick Messner, et al. "Imaging of myocardial infarction in dogs and humans using monoclonal antibodies specific for human myosin heavy chains." Journal of the American College of Cardiology 18, no. 2 (August 1991): 473–84. http://dx.doi.org/10.1016/0735-1097(91)90603-7.

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Alves, Bryce, Mary Anne Jelinek, Yanan Lu, Melissa Ritland, Patricia Velasco, Xi Zhao, Eddie Adams, and Joseph Fernandez. "Single B cell isolation and cloning from rabbits to generate recombinant antibodies." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 159.53. http://dx.doi.org/10.4049/jimmunol.204.supp.159.53.

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Abstract For decades the method for generating antibodies with high avidity and affinity relied upon monoclonal antibody generation from immunized mice or polyclonal antibodies from rabbits. Both methods have their shortcomings. The murine immune system—specifically the high degree of immunological tolerance—prevents robust humoral responses to antigens that closely reasonable self-antigens in the mouse. Additionally, the cost and time necessary to generate a monoclonal antibody from mice can be prohibitively expensive, particularly if multiple attempts at hybridoma generation are required. A work around is to generate polyclonal antibodies in rabbits. Rabbits are further evolutionarily removed from humans than mice and mount a stronger immunological response to immunized human proteins or antigens. Unfortunately, the source of polyclonal antibodies from each rabbit is finite. To combat this problem, here we describe the development of a method to isolate single rabbit plasma B cells after immunization. Once isolated the VH and VL regions of the antibody are sequenced and the sequences are cloned into a recombinant rabbit IgG and IgK backbone that enables the recombinant expression of the single cell-derived, cloned rabbit antibodies. In doing so we have harnessed the immunological response of the rabbit host while eliminating the supply problem of finite reactive serum volumes and the cost of traditional murine monoclonal antibody generation.

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Tilahun, Mulualem E., Govindarajan Rajagopalan, Nalini Shah-Mahoney, Rebecca G. Lawlor, Ashenafi Y. Tilahun, Chen Xie, Kannan Natarajan, et al. "Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies." Infection and Immunity 78, no. 6 (March 22, 2010): 2801–11. http://dx.doi.org/10.1128/iai.01121-09.

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ABSTRACT Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Igκ and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

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Nicolini, Fabio, Martine Bocchini, Davide Angeli, Giuseppe Bronte, Angelo Delmonte, Lucio Crinò, and Massimiliano Mazza. "Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting." Cancers 12, no. 4 (April 8, 2020): 915. http://dx.doi.org/10.3390/cancers12040915.

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Immunotherapy is the most promising therapeutic approach against malignant pleural mesothelioma (MPM). Despite technological progress, the number of targetable antigens or specific antibodies is limited, thus hindering the full potential of recent therapeutic interventions. All possibilities of finding new targeting molecules must be exploited. The specificity of targeting is guaranteed by the use of monoclonal antibodies, while fully human antibodies are preferred, as they are functional and generate no neutralizing antibodies. The aim of this review is to appraise the latest advances in screening methods dedicated to the identification and harnessing of fully human antibodies. The scope of identifying useful molecules proceeds along two avenues, i.e., through the antigen-first or binding-first approaches. The first relies on screening human antibody libraries or plasma from immunized transgenic mice or humans to isolate binders to specific antigens. The latter takes advantage of specific binding to tumor cells of antibodies present in phage display libraries or in responders’ plasma samples without prior knowledge of the antigens. Additionally, next-generation sequencing analysis of B-cell receptor repertoire pre- and post-therapy in memory B-cells from responders allows for the identification of clones expanded and matured upon treatment. Human antibodies identified can be subsequently reformatted to generate a plethora of therapeutics like antibody-drug conjugates, immunotoxins, and advanced cell-therapeutics such as chimeric antigen receptor-transduced T-cells.

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Lombe, Boniface Pongombo, Takeshi Saito, Hiroko Miyamoto, Akina Mori-Kajihara, Masahiro Kajihara, Masayuki Saijo, Justin Masumu, Takanari Hattori, Manabu Igarashi, and Ayato Takada. "Mapping of Antibody Epitopes on the Crimean-Congo Hemorrhagic Fever Virus Nucleoprotein." Viruses 14, no. 3 (March 6, 2022): 544. http://dx.doi.org/10.3390/v14030544.

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Crimean-Congo hemorrhagic fever virus (CCHFV), a nairovirus, is a tick-borne zoonotic virus that causes hemorrhagic fever in humans. The CCHFV nucleoprotein (NP) is the antigen most used for serological screening of CCHFV infection in animals and humans. To gain insights into antibody epitopes on the NP molecule, we produced recombinant chimeric NPs between CCHFV and Nairobi sheep disease virus (NSDV), which is another nairovirus, and tested rabbit and mouse antisera/immune ascites, anti-NP monoclonal antibodies, and CCHFV-infected animal/human sera for their reactivities to the NP antigens. We found that the amino acids at positions 161–320 might include dominant epitopes recognized by anti-CCHFV IgG antibodies, whereas cross-reactivity between anti-CCHFV and anti-NSDV antibodies was limited. Their binding capacities were further tested using a series of synthetic peptides whose sequences were derived from CCHFV NP. IgG antibodies in CCHFV-infected monkeys and patients were reactive to some of the synthetic peptide antigens (e.g., amino acid residues at positions 131–150 and 211–230). Only a few peptides were recognized by IgG antibodies in the anti-NSDV serum. These results provide useful information to improve NP-based antibody detection assays as well as antigen detection tests relying on anti-NP monoclonal antibodies.

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Holzer, Barbara, Pramila Rijal, Adam McNee, Basudev Paudyal, Veronica Martini, Becky Clark, Tanuja Manjegowda, et al. "Protective porcine influenza virus-specific monoclonal antibodies recognize similar haemagglutinin epitopes as humans." PLOS Pathogens 17, no. 3 (March 4, 2021): e1009330. http://dx.doi.org/10.1371/journal.ppat.1009330.

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Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations.

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Golden, Joseph W., Charles J. Shoemaker, Michael E. Lindquist, Xiankun Zeng, Sharon P. Daye, Janice A. Williams, Jun Liu, et al. "GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection." Science Advances 5, no. 7 (July 2019): eaaw9535. http://dx.doi.org/10.1126/sciadv.aaw9535.

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Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease but the protective efficacy of antibodies has never been evaluated in adult animal models. Here, we used adult mice to investigate the protection provided against CCHFV infection by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs). We identified a single non-neutralizing antibody (mAb-13G8) that protected adult type I interferon–deficient mice >90% when treatment was initiated before virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection failed to confer protection regardless of immunoglobulin G subclass. The target of mAb-13G8 was identified as GP38, one of multiple proteolytically cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein. This study reveals GP38 as an important antibody target for limiting CCHFV pathogenesis and lays the foundation to develop immunotherapeutics against CCHFV in humans.

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46

Duerr and Gorny. "V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers." Animals 9, no. 8 (August 3, 2019): 526. http://dx.doi.org/10.3390/ani9080526.

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Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

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Duerr, Ralf, and Miroslaw K. Gorny. "V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers." Vaccines 7, no. 3 (August 6, 2019): 82. http://dx.doi.org/10.3390/vaccines7030082.

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Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

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Zheng, Qingbing, Lin Xia, Wai Lan Wu, Zhenhua Zheng, Yongting Huo, Jun Wu, Yanning Liu, et al. "Properties and Therapeutic Efficacy of Broadly Reactive Chimeric and Humanized H5-Specific Monoclonal Antibodies against H5N1 Influenza Viruses." Antimicrobial Agents and Chemotherapy 55, no. 4 (January 18, 2011): 1349–57. http://dx.doi.org/10.1128/aac.01436-10.

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ABSTRACTHighly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad-spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection.

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Chapman, Nathaniel S., Haiyan Zhao, Nurgun Kose, Jonna B. Westover, Birte Kalveram, Robin Bombardi, Jessica Rodriguez, et al. "Potent neutralization of Rift Valley fever virus by human monoclonal antibodies through fusion inhibition." Proceedings of the National Academy of Sciences 118, no. 14 (March 29, 2021): e2025642118. http://dx.doi.org/10.1073/pnas.2025642118.

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Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn–specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.

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Hemachandra, Sonali, Kulwant Kamboj, Janna Copfer, Gerald Pier, Larry L. Green, and John R. Schreiber. "Human Monoclonal Antibodies againstPseudomonas aeruginosa Lipopolysaccharide Derived from Transgenic Mice Containing Megabase Human Immunoglobulin Loci Are Opsonic and Protective against Fatal Pseudomonas Sepsis." Infection and Immunity 69, no. 4 (April 1, 2001): 2223–29. http://dx.doi.org/10.1128/iai.69.4.2223-2229.2001.

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ABSTRACT Pseudomonas aeruginosa is a significant human pathogen, and no vaccine is commercially available. Passive antibody prophylaxis using monoclonal antibodies (MAb) against protectiveP. aeruginosa epitopes is an alternative strategy for preventing P. aeruginosa infection, but mouse MAb are not suitable for use in humans. Polyclonal human antibodies from multiple donors have variable antibody titers, and human MAb are difficult to make. We used immunoglobulin-inactivated transgenic mice reconstituted with megabase-size human immunoglobulin loci to generate a human MAb against the polysaccharide (PS) portion of the lipopolysaccharide O side chain of a common pathogenic serogroup ofP. aeruginosa, 06ad. The anti-PS human immunoglobulin G2 MAb made from mice immunized with heat-killed P. aeruginosa was specific for serogroup 06ad pseudomonas. The MAb was highly opsonic for the uptake and killing of P. aeruginosa by human polymorphonuclear leukocytes in the presence of human complement. In addition, 25 μg of the MAb protected 100% of neutropenic mice from fatal P. aeruginosasepsis. DNA sequence analysis of the genes encoding the MAb revealed VH3 and Vκ2/A2 variable-region genes, similar to variable-region genes in humans immunized with bacterial PS and associated with high-avidity anti-PS antibodies. We conclude that human MAb to P. aeruginosa made in these transgenic mice are highly protective and that these mice mimic the antibody response seen in humans immunized with T-cell-independent antigens such as bacterial PS.

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