Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

Abstract

Introduction: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. Areas covered: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. Expert opinion: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

“…From huge amount of ADCs, loncastuximab tesirine, anti-CD19 ADC, is the only one that has been approved for RR DLBCL as a single agent [ 34 ]. Other ADCs used for aggressive B-NHL subsets work more effectively in combination with standard chemoimmunotherapy (e.g., PV plus R-CHP, BV plus R-CHP, BV plus BR) [ 19 , 31 , 52 ]. Furthermore, long-lasting follow-up is being awaited for chemotherapy-free regimens such as BV plus nivolumab in RR PMBCL [ 88 ], triplet of PV plus rituximab and lenalidomide in RR DLBCL [ 14 ], PV plus obinutuzumab and lenalidomide [ 15 ] or PV plus Ven [ 32 ] in RR FL.…”

“…Overall response rate (ORR) was 45% (18/40) versus 18% (7/40), complete response (CR) was 40% (16/40) versus 18% (7/40), duration of response (DOR) was 10.3 versus 4.1 months, median progression free survival (PFS) was 7.6 versus 2.0 months and overall survival (OS) was 12.4 versus 4.7 months in RR DLBCL, but there was no benefit in RR FL patients [ 12 , 29 ]. Based on the results of this study, PV in combination with BR was approved for the treatment of transplant ineligible RR DLBCL patients after at least one (Europe) or two (USA) prior lines of therapy in combination with BR in 2019 [ 31 ].…”

Antibody‐Drug‐Conjugate Therapy for Hematological Cancers: Matching Cell Biology with Clinical Benefit

“…[153] Although this parameter may be less relevant for many HMs, the issue of presumptive conjugate degradation is still important. This has prompted intensive efforts to develop linkers that are only degraded by intracellular enzymes, [166] the fruits of which effort can be seen particularly in the more recently approved ADCs such as Besponsa, Polivy, and Blenrep, where the adverse side effect profile has improved, despite the use of highly toxic drugs. Intracellular site-specific degradation does come at the expense of limiting the so-called bystander effect.…”

Innovations in Antibody-Drug Conjugate (ADC) in the Treatment of Lymphoma

“…Once Polatuzumab binds to CD79b, it is internalized by endocytosis and directed to the lysosomes, where the linker cleavage occurs, resulting in the payload's release into the cells to induce apoptosis [87]. The structure and mechanism of action of PV is illustrated in Figure 4 [88]. PV consists of a monoclonal antibody that targets the antigen CD79b on a lymphoma cell.…”

“…The linker is then cleaved to release MMAE (payload), which in turn results in mitosis arrest in the nucleus and cellular death. Reprinted/adapted with permission from reference [88]. Copyright year: 2020, copyright name: American Society of Clinical Oncology.…”