Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target

Kroenke, Mark A.; Barger, Troy E.; Hu, Jenny; Miller, Mieke Jill; Kalenian, Kevin; He, Lin; Hsu, Hailing; Bartley, Yessenia; Chow, Vincent; Santos, Márcia Cristina Teixeira dos; Sullivan, Barbara A.; Cheng, Leonard K.; Parnes, Jane R.; Padaki, Rupa; Kuhns, Scott; Mytych, Daniel T.

doi:10.3389/fimmu.2021.782788

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…This was also observed for another TNF antagonist: a bi-specific antibody targeting TNF and TL1A, another trimeric protein of the same family. Immune complexes with this bi-specific antibody were associated with higher ADA response in 53/54 healthy donors administered with the compound ( 65 ). Thus, TNF concentrations, compounded by the individual genetic- and proteomic-background, may affect HLAII-levels of presentation upon formation of immune complexes with antagonists.…”

Section: Discussionmentioning

confidence: 99%

HLAII peptide presentation of infliximab increases when complexed with TNF

et al. 2022

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CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.

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Section: Discussionmentioning

confidence: 99%

HLAII peptide presentation of infliximab increases when complexed with TNF

et al. 2022

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“…BsAbs stimulate the immune system to generate a robust anti-tumor response, which may lead to undesired reactions. Nevertheless, immunotherapy is the standard treatment for selected types of cancers [67,74,75].…”

Section: Risk Factors Associated With the Antibodymentioning

confidence: 99%

“…Large immune complexes can also directly crosslink B cell receptors, leading to their activation and the production of antibodies. The stoichiometric relationships of the drug are crucial and can influence the formation of immune complexes [75][76][77].…”

Section: Risk Factors Associated With the Antibodymentioning

confidence: 99%

Double hit — bispecific antibodies in cancer therapy

Bogdanowicz,

Wojas-Krawczyk,

Krzyżanowska

et al. 2024

Oncol Clin Pract

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Immunotherapy has emerged as a promising strategy for cancer treatment, with bispecific antibodies (BsAbs) demonstrating significant therapeutic potential. BsAbs are biological molecules capable of simultaneously binding to two distinct antigens, allowing the immune response to target cancer cells precisely. However, despite promising results in preclinical studies and early clinical trials, immunotherapy based on these antibodies faces several significant issues that require careful consideration. One of them is the development of therapy resistance, which often leads to a loss of treatment effectiveness. Another challenge is the associated toxicity of immunotherapy. While BsAbs are designed to limit adverse effects, there remains a risk of side effects that can impact the quality of life for patients. Furthermore, it should be noted that the production of BsAbs is burdened with significant costs and involves complex processes, negatively affecting the accessibility of this therapy for the majority of patients. Hence, continuous efforts are necessary to develop more efficient and cost-effective methods for producing these antibodies to enable a broader range of patients to benefit from this innovative therapy.

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“…While there are no examples yet of this phenomenon in the oncology space, there are many examples of associations between IC formation and immunogenicity for anti-inflammatory drugs. [53][54][55][56][57] The formation of large ICs between the antibody drug and multimeric soluble targets may result in increased immunogenicity owing to enhanced uptake of the therapeutic agent by APCs. Large ICs can also directly cross-link B-cell receptors, leading to T cell-independent B-cell activation and antibody formation.…”

Section: Ic Formation Between Bsabs and Multimeric Soluble Targetsmentioning

confidence: 99%

“…58 59 Since the drug-to-target stoichiometric ratios can affect IC formation and subsequent ADA development in the clinic, complex formation can be assessed by standard methods such as size-exclusion chromatography when designing BsAbs candidates targeting ligands which could exist as soluble multimers. 54 Immunogenicity risk due to synergistic immunostimulatory drug MOA Immune checkpoint inhibitors Drugs with immunostimulatory activity may have a greater likelihood of inducing immunogenicity compared with drugs with known immunosuppressive MOA. Despite this possibility, monotherapies of multiple immune checkpoint inhibitors (e.g., anti-PD-1 mAbs and anti-CTLA-4 mAbs) have shown low ADA incidence.…”

Section: Ic Formation Between Bsabs and Multimeric Soluble Targetsmentioning

confidence: 99%

Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology

Zhou

Penny

Kroenke

et al. 2022

J Immunother Cancer

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With increasing numbers of bispecific antibodies (BsAbs) and multispecific products entering the clinic, recent data highlight immunogenicity as an emerging challenge in the development of such novel biologics. This review focuses on the immunogenicity risk assessment (IgRA) of BsAb-based immunotherapies for cancer, highlighting several risk factors that need to be considered. These include the novel scaffolds consisting of bioengineered sequences, the potentially synergistic immunomodulating mechanisms of action (MOAs) from different domains of the BsAb, as well as several other product-related and patient-related factors. In addition, the clinical relevance of anti-drug antibodies (ADAs) against selected BsAbs developed as anticancer agents is reviewed and the advances in our knowledge of tools and strategies for immunogenicity prediction, monitoring, and mitigation are discussed. It is critical to implement a drug-specific IgRA during the early development stage to guide ADA monitoring and risk management strategies. This IgRA may include a combination of several assessment tools to identify drug-specific risks as well as a proactive risk mitigation approach for candidate or format selection during the preclinical stage. The IgRA is an on-going process throughout clinical development. IgRA during the clinical stage may bridge the gap between preclinical immunogenicity prediction and clinical immunogenicity, and retrospectively guide optimization efforts for next-generation BsAbs. This iterative process throughout development may improve the reliability of the IgRA and enable the implementation of effective risk mitigation strategies, laying the foundation for improved clinical success.

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Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target

Cited by 9 publications

References 36 publications

HLAII peptide presentation of infliximab increases when complexed with TNF

HLAII peptide presentation of infliximab increases when complexed with TNF

Double hit — bispecific antibodies in cancer therapy

Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology

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