Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges

Brummelen, Emilie M.J. van; Ros, Willeke; Wolbink, Gertjan; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1634/theoncologist.2016-0061

Cited by 96 publications

(92 citation statements)

References 69 publications

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“…It is relevant that anti-drug antibodies have been reported in many trials using recombinant proteins and antibodies. 24 In one study, anti-IL-2 antibodies were detected in roughly half of patients, and development of these antibodies was not associated with a decrease in the treatment effect. 25 …”

Section: Discussionmentioning

confidence: 95%

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

Wrangle

Velcheti

Patel

et al. 2018

The Lancet Oncology

332

290

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Background Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. Methods In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1–5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. Findings Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. Interpretation ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour act...

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Section: Discussionmentioning

confidence: 95%

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

Wrangle

Velcheti

Patel

et al. 2018

The Lancet Oncology

332

290

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“…We postulate that an antidrug antibody (ADA) has the potential to induce Fc receptor binding similar to an IgG cross-linker and induce degranulation. Because detection of ADA has been reported in 26% of oncology patients treated with a fully humanized antibody (39), an Fc-silent antibodies approach would likely not be feasible in the clinic because of the risk of ADA.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies

L'Italien¹,

Orozco²,

Abrams³

et al. 2018

Clinical Cancer Research

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Hypersensitivity reactions (HSRs) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcεR1, FcγR, and treatment with Fc silencing antibody formats. Transient elevation of serum tryptase was observed in patients 1-hour posttreatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcγ receptors revealed human PBC-MCs expressed both FcγRII and low levels of FcγRI. Interestingly, increasing the level of FcγRI upon addition of IFNγ, significantly enhanced LOP628-mediated mast cell degranulation. Our data suggest LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcγR and KIT, resulting in mast cell activation. .

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“…67 The report also found that even among agents on the market, gaps in the data on ADA formation were apparent. 67 Routine investigation of the relationship between ADAs and efficacy, toxicity, and PK may shed light on the clinical relevance of ADAs and help explain the variability seen in drug responses and safety. Standardized reporting of ADAs is critical to understanding the relevance of ADA formation, and the development of trials investigating clinical prevention strategies is needed.…”

Section: Antidrug Antibodiesmentioning

confidence: 99%

“…ADAs can also have toxic effects, including hypersensitivity reactions . A recent ADA‐focused review of extracted data from 81 oncology clinical trials of biologic agents reported most biological anticancer immunotherapy drugs are immunogenic and induce ADAs . The report also found that even among agents on the market, gaps in the data on ADA formation were apparent .…”

Section: Mechanisms Of Resistance To Cd3‐bispecific Antibodiesmentioning

confidence: 99%

“…A recent ADA‐focused review of extracted data from 81 oncology clinical trials of biologic agents reported most biological anticancer immunotherapy drugs are immunogenic and induce ADAs . The report also found that even among agents on the market, gaps in the data on ADA formation were apparent . Routine investigation of the relationship between ADAs and efficacy, toxicity, and PK may shed light on the clinical relevance of ADAs and help explain the variability seen in drug responses and safety.…”

Section: Mechanisms Of Resistance To Cd3‐bispecific Antibodiesmentioning

confidence: 99%

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Bispecific Antibodies in the Treatment of Hematologic Malignancies

Duell

Lammers

Djuretic

et al. 2019

Clin Pharma and Therapeutics

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Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single‐agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single‐agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.

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Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges

Cited by 96 publications

References 69 publications

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies

Bispecific Antibodies in the Treatment of Hematologic Malignancies

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