The immunogenicity of humanized and fully human antibodies

Harding, Fiona; Stickler, Marcia; Razo, Jennifer; DuBridge, Robert B.

doi:10.4161/mabs.2.3.11641

Cited by 592 publications

(272 citation statements)

References 79 publications

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“…Because each fully human therapeutic antibody has its own inherent immunogenicity caused by its particular sequence [369], this immunogenicity is to be determined in part by the sequence of its CDRs. Adalimumab, a fully human antibody, has been reported to induce an antibody production in a subset of patients (5-89) % that varies depending on the situation, and a reduction in therapeutic efficacy was observed in the antibody-positive patients [394][395][396][397]. This significant immunogenicity of adalimumab was supported by the presence of effector T-cell epitopes in regions containing a CDR sequence determined by an in vitro helper CD4+ T-cell assay.…”

Section: Fully Human Mabsmentioning

confidence: 77%

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Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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Section: Fully Human Mabsmentioning

confidence: 77%

“…Additionally, in vitro CD4+ helper T-cell assays can be used to identify effector T-cell epitopes [395]; a disadvantage of this in vitro assay is, however, its low throughput. A combination of both procedures (i.e.…”

Section: In Silico and In Vitro Deimmunization Technologiesmentioning

confidence: 99%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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“…The resulting percentage of human residues in Vk, identified by IMGT/ DomainGapAlign, is 90.5»92.3%, which is comparable to approved fully human antibodies and qualifies the name "-umab" according to the current World Health Organization (WHO) International Nonproprietary Name (INN) definitions; whereas the percentage of human residues in VH is 77.8»83.8%, which is similar to the currently approved humanized antibodies (-zumab), but is less than 85% and could also fall into the "chimeric" category (-ximab). 38 To further reduce the immunogenicity, one can consider removing T-cell epitopes 8,39,40 from the grafted combined Kabat/IMGT/Paratome CDRs, where it is the major immunogenic site that we have seen in humanized murine antibodies. 8 Anti-mesothelin immunotoxins have been developed for clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…7 To enable the successful development of RabMAbs as therapeutics, the antibodies should be humanized, which can reduce the chance that patients will produce neutralizing antibodies to the non-human molecules. 8 The current methods for mouse antibody humanization include complementary-determining region (CDR) grafting, [9][10][11][12] specificity-determining residues (SDR) grafting, 13 phage display, 14 and de-immunization. 8,15,16 The CDR grafting is the first-used and clinically validated humanization technique.…”

Section: Introductionmentioning

confidence: 99%

“…8 The current methods for mouse antibody humanization include complementary-determining region (CDR) grafting, [9][10][11][12] specificity-determining residues (SDR) grafting, 13 phage display, 14 and de-immunization. 8,15,16 The CDR grafting is the first-used and clinically validated humanization technique. 9,12,17 This method was successfully used to humanize murine antibody 4D5 (anti-human epidermal growth factor receptor 2), which was then developed as trastuzumab (Herceptin Ò , Genentech, Inc., South San Francisco, California).…”

Section: Introductionmentioning

confidence: 99%

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Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples

Zhang

2017

mAbs

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Rabbit monoclonal antibodies (RabMAbs) can recognize diverse epitopes, including those poorly immunogenic in mice and humans. However, there have been only a few reports on RabMAb humanization, an important antibody engineering step usually done before clinical applications are investigated. To pursue a general method for humanization of RabMAbs, we analyzed the complex structures of 5 RabMAbs with their antigens currently available in the Protein Data Bank, and identified antigen-contacting residues on the rabbit Fv within the 6 Angstrom distance to its antigen. We also analyzed the supporting residues for antigen-contacting residues on the same heavy or light chain. We identified "HV4" and "LV4" in rabbit Fvs, non-complementarity-determining region (CDR) loops that are structurally close to the antigen and located in framework 3 of the heavy chain and light chain, respectively. Based on our structural and sequence analysis, we designed a humanization strategy by grafting the combined Kabat/IMGT/Paratome CDRs, which cover most antigen-contacting residues, into a human germline framework sequence. Using this strategy, we humanized 4 RabMAbs that recognize poorly immunogenic epitopes in the cancer target mesothelin. Three of the 4 humanized rabbit Fvs have similar or improved functional binding affinity for mesothelin-expressing cells. Interestingly, 4 immunotoxins composed of the humanized scFvs fused to a clinically used fragment of Pseudomonas exotoxin (PE38) showed stronger cytotoxicity against tumor cells than the immunotoxins derived from their original rabbit scFvs. Our data suggest that grafting the combined Kabat/IMGT/Paratome CDRs to a stable human germline framework can be a general approach to humanize RabMAbs.

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Immunogenicity With Ranibizumab Biosimilar SB11 (Byooviz) and Reference Product Lucentis and Association With Efficacy, Safety, and Pharmacokinetics

Bressler

Kim

et al. 2023

JAMA Ophthalmol

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ImportanceSB11 and reference ranibizumab (RBZ) are monoclonal anti–vascular endothelial growth factor (VEGF)–A antibodies approved for the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. The association of ranibizumab immunogenicity and treatment outcomes in patients with nAMD is unclear but relevant regarding concerns about immunogenicity of anti-VEGF biological products.ObjectiveTo examine the association of immunogenicity to ranibizumab products (SB11 and RBZ) with efficacy, safety, and pharmacokinetics.Design, Setting, and ParticipantsThis was a post hoc analysis of a randomized, double-masked, parallel-group phase 3 equivalence study with participants from 75 centers in 9 countries conducted from March 14, 2018, to December 9, 2019. Included were participants 50 years or older with nAMD and active subfoveal choroidal neovascularization lesions.InterventionsIntravitreal injection of SB11 or RBZ, 0.5 mg, every 4 weeks through week 48.Main Outcomes and MeasuresSerum antidrug antibodies (ADAs) were analyzed during the study period until week 52 to measure immunogenicity. Analyses were performed on immunogenicity (overall ADA positivity) with best-corrected visual acuity (BCVA) and central subfield thickness (CST). Adverse events associated with intraocular inflammation (IOI) and serum ranibizumab levels were compared between overall ADA-positive and ADA-negative participants.ResultsA total of 705 participants (mean [SD] age, 74.1 [8.5] years; 403 female individuals [57.2%]) were included in the study. The overall incidence of ADA-positivity was 32 of 657 (4.9%) at week 52. The least-squares mean (SE) differences between overall ADA-positive and ADA-negative participants up to week 52 for BCVA and CST, respectively, were 1.6 (2.2) letters (95% CI, −2.7 to 5.8; P = .46) and 3 (13) μm (95% CI, −23 to 29; P = .83). IOI-related events occurred in 1 of 32 overall ADA-positive participants (3.1%) and 4 of 620 overall ADA-negative participants (0.6%). Mean (SD) serum ranibizumab concentrations over time were slightly lower in overall ADA-positive participants compared with those of ADA-negative participants, with a maximum value of 1389.3 (875.4) pg/mL at week 16 vs 1665.4 (1124.0) pg/mL at week 36, respectively.Conclusions and RelevanceResults of this post hoc analysis of an equivalence trial suggest that immunogenicity was not associated with efficacy and safety of SB11 and RBZ in participants with nAMD. With a low overall ADA incidence, no clear association was identified between overall ADA positivity and pharmacokinetics. These findings support the biosimilarity of SB11 and RBZ, with no safety concern identified for SB11 vs RBZ associated with immunogenicity.Trial RegistrationClinicalTrials.gov Identifier: NCT03150589

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The immunogenicity of humanized and fully human antibodies

Cited by 592 publications

References 79 publications

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples

Immunogenicity With Ranibizumab Biosimilar SB11 (Byooviz) and Reference Product Lucentis and Association With Efficacy, Safety, and Pharmacokinetics

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