A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies

Bartlett, Nancy L.; Younes, Anas; Carabasi, Matthew; Forero, Andres; Rosenblatt, Joseph D.; Leonard, John P.; Bernstein, Steven H.; Bociek, R. Gregory; Lorenz, Jennie M.; Hart, Bruce W.; Barton, Jeremy

doi:10.1182/blood-2007-07-099317

Cited by 183 publications

(105 citation statements)

References 32 publications

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“…Despite this selectivity, the clinical benefit of anti-CD30 immunotherapy in HL patients is poor. 1,2 This is at least in part due to CD30 shedding that leads to the generation of a soluble serum competitor. 3,4 In addition, aberrant transcription factor nuclear factor-kB survival activity, governed by the overexpression of nuclear factor-kB-inducing kinase, is a hallmark of HL and participates in apoptosis resistance of tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Vahdat¹,

Reiners²,

Simhadri³

et al. 2009

Leukemia

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Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-a-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.

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Section: Introductionmentioning

confidence: 99%

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Vahdat¹,

Reiners²,

Simhadri³

et al. 2009

Leukemia

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“…Despite the promising preclinical activity of this drug [55], its clinical activity in patients with relapsed/refractory HL has been limited ( Table 1). A phase I study in relapsed/refractory CD30+ hematologic malignancies demonstrated that a single dose was safe and generally well tolerated [56,57]. In the phase II portion of a subsequent multidose phase I/II study [58,59], some disease stabilizations but no remissions occurred among 35 evaluable, heavily pretreated HL patients [59], and the HL arm was therefore closed [60].…”

Section: Unconjugated Anti-cd30 Antibodiesmentioning

confidence: 99%

Immunotherapies for Hodgkin's lymphoma

Kasamon

Ambinder

2008

Critical Reviews in Oncology/Hematology

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“…42 For example, brentuximab vedotin has a serum half-life of 4 to 6 days, yet unconjugated SGN-30 mAb has a halflife of 1 to 3 weeks. 17,43 The chemical properties of drug linkers also impact ADC stability, as disulfidelinked T-SPP-DM1 cleared approximately 2-fold faster in mice than thioether-linked ado-trastuzumab emtansine, despite comparable clearance of the respective total antibodies. 44 Increased DAR can also shorten serum half-life, suggesting the number of payloads may also influence catabolism.…”

Section: Disposition and Metabolic Fate Of Adcsmentioning

confidence: 99%

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

Vezina

Cotreau

Han

et al. 2017

The Journal of Clinical Pharma

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Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in-human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion.

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A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies

Cited by 183 publications

References 32 publications

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Immunotherapies for Hodgkin's lymphoma

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

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