Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma

Goldberg, Jacob L.; Navid, Fariba; Hank, J.; Erbe, Amy K.; Santana, Víctor M.; Gan, Jacek; Bie, Fenna De; Javaid, Amal M.; Hoefges, Anna; Merdler, Michael; Carmichael, Lakeesha; Kim, KyungMann; Bishop, Michael W.; Meager, Michael M; Gillies, S. D.; Pandey, Janardan P.; Sondel, Paul M.

doi:10.1136/jitc-2020-000590

Cited by 3 publications

(1 citation statement)

References 24 publications

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“…More recently, allotypes have been investigated for their potential role as immunogenic motifs in therapeutic antibodies. Surprisingly, it appears that allotypes act only as minor epitopes in monoclonal antibodies and do not appear to elicit acute rejection ( 12 ), although some studies have reported low levels of pre-existing circulating antibodies against allotypes of therapeutic monoclonals ( 13 , 14 ). A key pitfall of serological detection of allotypes is the difficulty of evaluating immunogenic responses to immunoglobulin isotypes expressed at low levels in serum, such as IgE and IgM, signified by a lack of known allotypes for these classes ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

Warrender

Kelton

2020

Front. Immunol.

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Polymorphic diversity in antibody constant domains has long been defined by allotypic motifs that cross react with the sera of other individuals. Improvements in sequencing technologies have led to the discovery of a large number of new allelic sequences that underlie this diversity. Many of the point mutations lie outside traditional allotypic motifs suggesting they do not elicit immunogenic responses. As antibodies play an important role in immune defense and biotechnology, understanding how this newly resolved diversity influences the function of antibodies is important. This review investigates the current known diversity of antibody alleles at a protein level for each antibody isotype as well as the kappa and lambda light chains. We focus on evidence emerging for how these mutations perturb antibody interactions with antigens and Fc receptors that are critical for function, as well as the influence this might have on the use of antibodies as therapeutics and reagents.

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Section: Introductionmentioning

confidence: 99%

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

Warrender

Kelton

2020

Front. Immunol.

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Living in LALA land? Forty years of attenuating Fc effector functions

Hale

2024

Immunological Reviews

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SummaryThe Fc region of antibodies is vital for most of their physiological functions, many of which are engaged through binding to a range of Fc receptors. However, these same interactions are not always helpful or wanted when therapeutic antibodies are directed against self‐antigens, and can sometimes cause catastrophic adverse reactions. Over the past 40 years, there have been intensive efforts to “silence” unwanted binding to Fc‐gamma receptors, resulting in at least 45 different variants which have entered clinical trials. One of the best known is “LALA” (L234A/L235A). However, neither this, nor most of the other variants in clinical use are completely silenced, and in addition, the biophysical properties of many of them are compromised. I review the development of different variants to see what we can learn from their biological properties and use in the clinic. With the rise of powerful new uses of antibody therapy such as bispecific T‐cell engagers, antibody‐drug conjugates, and checkpoint inhibitors, it is increasingly important to optimize the Fc region as well as the antibody binding site in order to achieve the best combination of safety and efficacy.

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The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches

Polychronopoulos,

Bedoya-Reina,

Johnsen

2024

Cancers

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Neuroblastoma is a peripheral nervous system tumor that almost exclusively occurs in young children. Although intensified treatment modalities have led to increased patient survival, the prognosis for patients with high-risk disease is still around 50%, signifying neuroblastoma as a leading cause of cancer-related deaths in children. Neuroblastoma is an embryonal tumor and is shaped by its origin from cells within the neural crest. Hence, neuroblastoma usually presents with a low mutational burden and is, in the majority of cases, driven by epigenetically deregulated transcription networks. The recent development of Omic techniques has given us detailed knowledge of neuroblastoma evolution, heterogeneity, and plasticity, as well as intra- and intercellular molecular communication networks within the neuroblastoma microenvironment. Here, we discuss the potential of these recent discoveries with emphasis on new treatment modalities, including immunotherapies which hold promise for better future treatment regimens.

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Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma

Cited by 3 publications

References 24 publications

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

Living in LALA land? Forty years of attenuating Fc effector functions

The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches

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