The Proteolytic Cleavage of Therapeutic Monoclonal Antibody Hinge Region: More Than a Matter of Subclass

Deveuve, Quentin; Lajoie, Laurie; Barrault, Benjamin; Thibault, Gilles

doi:10.3389/fimmu.2020.00168

Cited by 30 publications

(22 citation statements)

References 36 publications

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“…Since the frequency of irAEs is higher in female patients than that in male patients (35-37), ICPI-induced nephritis might have different mechanism to that of other irAEs. Since ipilimumab has an immunoglobulin G 1 (IgG 1 ) structure, it might lead to higher activation of complement and other immune system factors than the rest of the IgG subtypes (38)(39)(40). Therefore, our results suggested that male patients or patients with concomitant use of ICPIs and PPIs (excluded vonoprazan) should be monitored for renal function after chemotherapy.…”

Section: Discussionmentioning

confidence: 92%

Concomitant Proton Pump Inhibitors and Immune Checkpoint Inhibitors Increase Nephritis Frequency

Kato

Mizuno

Koseki

et al. 2021

In Vivo

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Background/Aim: Concomitant proton pump inhibitor (PPI) and immune checkpoint inhibitor (ICPI) were determined as risk factors of acute kidney injury. To identify the type of PPI associated with ICPI-induced nephritis, we used the Japanese Adverse Drug Event Report database. Patients and Methods: ICPIs (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, and avelumab) and PPIs (esomeprazole, omeprazole, vonoprazan, rabeprazole, and lansoprazole) were selected as suspected nephritis-inducing drugs. Results: The cases of concomitant use of atezolizumab and rabeprazole, ipilimumab and omeprazole, ipilimumab and lansoprazole, nivolumab and esomeprazole, nivolumab and omeprazole, nivolumab and rabeprazole, nivolumab and lansoprazole, pembrolizumab and esomeprazole, as well as pembrolizumab and lansoprazole had a significantly higher reported odds ratio than monotherapy cases. Conclusion: Male patients or patients using ICPIs and PPIs (excluded vonoprazan) concomitantly should be monitored for renal function after chemotherapy.Immune checkpoint inhibitors (ICPIs) are used as essential anti-cancer chemotherapy in various types of cancers (1-5). Blockade of programmed cell death-1 (PD-1)/PD-ligand-1 signaling (6, 7) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling (8) activates T-cell mediated antitumor immunity; therefore, ICPIs exert dramatic effects in patients with cancer expressing these proteins. As ICPIs induce antitumor effects by reactivating antitumor immunity, they also cause immune-related adverse events (irAEs), such as interstitial pneumonia and nephritis (9-11), thyroid dysfunction (5, 9), type 1 diabetes mellitus (5), and lupus erythematosus (12). The clinical features and outcomes of ICPI-induced acute kidney injury (AKI) have been reported (13-15). As a pathological feature, acute tubulointerstitial nephritis was the primary pathologic lesion with lymphocyte infiltration. In addition, lower baseline estimated glomerular filtration rate (eGFR), use of proton pump inhibitor (PPI), and ICPI combination were determined as risk factors of ICPI-associated AKI (13). Furthermore, the mortality of patients with renal recovery after ICPI-induced nephritis was better than that of patients without renal recovery (16). To improve prognosis for patients treated with ICPIs, the prevention of ICPI-induced nephritis is essential.PPIs are traditionally widely used for the treatment of several acid-related disorders, including peptic ulcer disease, gastroesophageal reflux disease, and Helicobacter pylori eradication. Although the use of PPIs was perceived as safe, it is associated with the incidence of AKI (17-22). In particular, omeprazole is associated with acute interstitial nephritis (AIN) (17). Because AKI and AIN increase the risk of chronic kidney disease (CKD), the prevention of PPIinduced AIN could decrease the initiation of dialysis (23)(24)(25).Since the frequency of overall incidence of ICPI-induced AKI is 2.2% (26), the information regarding ICPI-induced AKI is limited. In a...

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Section: Discussionmentioning

confidence: 92%

Concomitant Proton Pump Inhibitors and Immune Checkpoint Inhibitors Increase Nephritis Frequency

Kato

Mizuno

Koseki

et al. 2021

In Vivo

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“…The hypothesis that the CH2 domain rotation persists in solution was supported by a recent experimental observation of the cleavage of reduced pembrolizumab, mediated by the immunoglobulin-degrading enzyme from Streptococcus pyogenes, which binds the CH2-CH3 interface. 41 The asymmetric orientation of the two CH2 domains can also explain the contact area between Fabs and Fc, reported in Figure S8. Here, the range of variability of the Fab1-Fc contact area greatly exceeds that of the Fab2-Fc pair, which remains low in the vast majority of the clusters; moreover, a significantly larger contact surface between Fab1 and Fc is observed in clusters 0 A and 0 H , with respect to the other cases.…”

Section: The Presence Of the Bound Antigen Restricts The Range Of Conformations Of The Full-length Pembrolizumabmentioning

confidence: 93%

How Communication Pathways Bridge Local and Global Conformations in an IgG4 Antibody: a Molecular Dynamics Study

Tarenzi

Rigoli

Potestio

2021

Preprint

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The affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recently, however, evidence has accumulated that points toward a nontrivial relation between the CDR and distal sites on the antibody structure: variations in the binding strengths have been observed upon mutating amino acids separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4 μs of MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR; a pivotal role in this relationship is played by the relatively short hinge, which mechanically couples Fab and Fc domains. These results support the hypothesis that pembrolizumab behaves as a complex machinery, with a multi-scale hierarchy of global and local conformational changes that communicate with one another. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.

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“…Proteases (MMP-3, MMP-12 and HNE) affect the integrity of anti-TNFα mAb and compromise their therapeutic capacities in comparison with intact mAb ( Biancheri et al, 2015 ; Curciarello et al, 2020 ). Proteolysis of mAbs (IgG1 and 4) by MMPs (MMP-12) and IdeS has been shown to be dependent on the incubation time ( Deveuve, Lajoie, Barrault, & Thibault, 2020 ), with long time exposition to proteases being responsible for a decreased efficacy of the anti-HER2 antibody pertuzumab ( Hsiao, Fan, Jordan, Zhang, & An, 2018 ; Kinder et al, 2013 ). A single proteolytic cleavage in the lower hinge of a humanized IgG1, trastuzumab, or pertuzumab, by MMP-12 also led to a loss of one of the Fc fractions, reducing its effector activity via the immune system and therefore its anti-tumour efficacy in vivo ( Fan et al, 2012 ; Hsiao et al, 2018 ; N. Zhang et al, 2015 ).…”

Section: Extracellular Barriersmentioning

confidence: 99%

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

Ojaimi

Blin

Lamamy

et al. 2022

Pharmacology & Therapeutics

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Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a remarkable expansion with an expected acceleration in 2021–2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients’ adherence to the treatment.

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The Proteolytic Cleavage of Therapeutic Monoclonal Antibody Hinge Region: More Than a Matter of Subclass

Cited by 30 publications

References 36 publications

Concomitant Proton Pump Inhibitors and Immune Checkpoint Inhibitors Increase Nephritis Frequency

Concomitant Proton Pump Inhibitors and Immune Checkpoint Inhibitors Increase Nephritis Frequency

How Communication Pathways Bridge Local and Global Conformations in an IgG4 Antibody: a Molecular Dynamics Study

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

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