Abstract
BackgroundCurrent anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. In addition to IgG1, three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models. Nonetheless, no therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes. In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively.ResultsIn vitro human IgG1 and IgG3 did not show any differences in opsonisation ability of B16F10-gp75 mouse melanoma cells. IgG1, however, was superior in inducing phagocytosis of tumour cells by mouse macrophages. Similarly, in a mouse peritoneal metastasis model we did not detect an improved effect of IgG3 in preventing tumour outgrowth. Moreover, replacing the arginine at position 435 for a histidine in IgG3 to enhance half-life did not result in better suppression of tumour outgrowth compared to wild type IgG3 when injected prior to tumour cell injection.ConclusionIn conclusion, human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model.
Highlights
The development of new and better monoclonal antibodies to use as therapy to treat cancer—in addition to chemo- and/ or radiotherapy—has increased dramatically in the last decade [1]. mAbs can be designed to interact with tumour-associated antigens, and initiate a wide range of effector mechanisms, which can potentially result in regression of the tumour
In addition to immunoglobulin G1 (IgG1), three more isotypes are present in humans, of which IgG3 has been found to be superior compared to human IgG1 in inducing antibody dependent cell cytotoxicity (ADCC), phagocytosis or activation of complement in some models
Human IgG3 does not have improved therapeutic efficacy compared to human IgG1 in a mouse tumour model
Summary
The development of new and better monoclonal antibodies (mAb) to use as therapy to treat cancer—in addition to chemo- and/ or radiotherapy—has increased dramatically in the last decade [1]. mAbs can be designed to interact with tumour-associated antigens, and initiate a wide range of effector mechanisms, which can potentially result in regression of the tumour. Current anti-cancer therapeutic antibodies that are used in the clinic are predominantly humanized or fully human immunoglobulin G1 (IgG1). These antibodies bind with high affinity to the target antigen and are efficient in activating the immune system via IgG Fc receptors and/or complement. No therapeutic human IgG3 mAbs have been developed due to the short in vivo half-life of most known IgG3 allotypes In this manuscript, we compared the efficacy of V-gene matched IgG1 and IgG3 anti-tumour mAb (TA99) in mice, using natural variants of human IgG3 with short- or long half-life, differing only at position 435 with an arginine or histidine, respectively
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