Development and Integration of Antibody–Drug Conjugate in Non-Hodgkin Lymphoma

Mehta, Amitkumar; Forero‐Torres, Andres

doi:10.1007/s11912-015-0466-9

Cited by 21 publications

(17 citation statements)

References 45 publications

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“…A more recent update of adult patients with B‐NHL reported a 33% ORR and a 22% complete response rate among patients with DLBCL ( n = 53), mantle cell lymphoma ( n = 5) and follicular lymphoma ( n = 3) (Moskowitz et al , ). Other antibody‐drug conjugates are currently in clinical development for adult patients with B‐cell lymphoma including polatuzumab vedotin, directed at CD79B, and pinatuzumab vedotin and inotuzumab ozogamacin, both directed at CD22 (Mehta & Forero‐Torres, ).…”

Section: Novel Targeted Therapiesmentioning

confidence: 99%

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Giulino‐Roth

Goldman

2016

Br J Haematol

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Paediatric B-cell non-Hodgkin lymphoma (B-NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource-rich countries, the expected cure rate is in excess of 85% with application of risk-adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high-risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B-NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B-NHL with a focus on how this may help guide future rational targeted therapy.

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Section: Novel Targeted Therapiesmentioning

confidence: 99%

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Giulino‐Roth

Goldman

2016

Br J Haematol

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“…For two decades now, rituximab has played an indispensable role in NHL treatment, indicated for use both as a single agent and alongside cytoreductive combination chemotherapy, e.g., R-CHOP [24] . As part of an evolution away from chemotherapy-based management of NHL, a number of clinical investigations of rituximab in combination with ADCs directed against other B-cell antigens are being explored [25] . To date, the most advanced of these have involved two CD22-targeting ADCs.…”

Section: Discussionmentioning

confidence: 99%

The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models

et al. 2017

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Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.

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“…22,23 ADCETRIS (brentuximab vedotin), approved for relapsed classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma, 24 also shows significant activity in DLBCL. 25 Many of the ADCs tested in relapsed/refractory DLBCL have shown single agent objective response rates of between 40% and 50%, but response durability is suboptimal, possibly owing to the fact that many patients achieved partial rather than complete responses.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Ryan¹,

Palanca-Wessels

Schimpf³

et al. 2017

Blood

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• SGN-CD19B is broadly active in vitro against malignant B-cell lines, including doublehit and triple-hit lymphoma cell lines.• SGN-CD19B shows significant antitumor activity in vivo in preclinical models of B-NHL and B-cell-derived acute lymphoblastic leukemia.Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 mg/kg (3 mg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mg/kg (1 mg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20 1 B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL.

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Development and Integration of Antibody–Drug Conjugate in Non-Hodgkin Lymphoma

Cited by 21 publications

References 45 publications

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

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