Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study

Palanca-Wessels, Maria Corinna; Czuczman, Myron S.; Salles, Gilles; Assouline, Sarit; Sehn, Laurie H.; Flinn, Ian W.; Patel, Manish R.; Sangha, Randeep; Hagenbeek, Anton; Advani, Ranjana H.; Tilly, Hervé; Casasnovas, Olivier; Press, Oliver W.; Yalamanchili, Sreeni; Kahn, Robert S.; Dere, Randall C.; Lü, Dan; Jones, Surai; Jones, Cheryl; Chu, Yu Waye; Morschhauser, Franck

doi:10.1016/s1470-2045(15)70128-2

Cited by 279 publications

(224 citation statements)

References 21 publications

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“…Indeed, a recent clinical trial using anti-CD79B antibody conjugate as a single agent or combined with rituximab had no clinical effect in CLL, but had an objective response in 14 of 24 DLBCL patients, and 6 of 7 patients with MCL. 59 The difference between CLL and MCL for a-BCR-induced signaling is striking, given that MCL and CLL are the 2 types of B-cell malignancies that respond clinically to the BTK inhibitor ibrutinib. [25][26][27][28] Ibrutinib might work in CLL by downregulating the constitutive BCR signaling that seems important for survival of CLL cells, whereas ibrutinib may work in MCL by inhibiting the potentiated BCR signaling characteristic of this malignancy.…”

Section: Discussionmentioning

confidence: 99%

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

Myklebust

Brody

Kohrt

et al. 2017

Blood

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• Contrasting patterns of basal phosphorylation levels and a-BCR-induced signaling between CLL and MCL tumors.• Direct association between BCR-induced signaling strength and CD79B level, but inverse association with BTK and SYK inhibitor efficacy.Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large Bcell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cg), but had low a-BCR-induced signaling. This contrasted MCL tumors, where a-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, a-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors. (Blood. 2017;129(6):759-770)

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Section: Discussionmentioning

confidence: 99%

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

Myklebust

Brody

Kohrt

et al. 2017

Blood

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“…44 However, the reduced uptake of cys-mcMMAF into nontargeted cells may mitigate toxicity, which could explain why SGN-CD19A shows reduced myelosuppression, minimal neuropathy, and improved overall tolerability when compared with other ADCs. 12,45 SGN-CD19B, on the other hand, offers the potential for robust activity against refractory B-cell malignancies but may induce more myelosuppression than SGN-CD19A. 12 We would not expect patients treated with SGN-CD19B to experience the ocular symptoms associated with certain auristatin and maytansine payloads 46 because these reversible ocular events are caused by nonantigen mediated uptake of ADC and are not associated with the PBD payload.…”

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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“…In a phase I study, this drug was administrated at escalating dose from 0.1 to 2.4 mg/kg for 34 NHL and 18 CLL patients [22]. The recommended dose for phase 2 trial was 2.4 mg/kg as a single agent and in combination with rituximab.…”

Section: Polatuzumab Vedotinmentioning

confidence: 99%

Recent Advances in Therapeutics for B-Cell Lymphoma

Terui¹

2018

JPP

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Abstract:Objectives: The molecular targeting drugs for the treatment of B-cell lymphoma have been dramatically developed. Recently, novel drugs of monoclonal antibodies and small molecules are approved by US FDA (Food and Drug Administration). Key Findings: This review summarizes characteristics, mechanisms, and results of the trials in the novel molecular targeting drugs for B-cell lymphoma such as obinutuzumab, polatuzumab vedotin, ibrutinib, idelalisib, and venetoclax. Summary: As a novel anti-CD20 antibody, obinutuzumab has been clinically developed on going. ADC (antibody drug conjugate) against CD79b molecules is also developed for B-cell lymphoma. BCR pathway is one of the most crucial pathways, and ibrutinib is a BTK (Bruton's tyrosine kinase) inhibitor that is under development for the treatment of B-cell malignancies, including CLL (chronic lymphocytic leukemia), MCL (mantle cell lymphoma), and DLBCL (diffuse large B-cell lymphoma), as well as FL (follicular lymphoma). BCL-2 family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax, which is a highly selective BCL-2 inhibitor, a mimic for its BCL2 homolog 3-domain to induce apoptosis, is also reported to be active against B-cell malignancies. Conclusions: Mechanism-based combination regimens including these drugs may be required in the future.

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Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study

Cited by 279 publications

References 21 publications

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

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

Recent Advances in Therapeutics for B-Cell Lymphoma

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