Novel Targeted Antibody-Drug Conjugates in Non-Hodgkin Lymphoma

Published: Monday, Jun 18, 2018
Blood cells
Antibody-drug conjugates (ADCs) represent a targeted class of agents with an improved therapeutic index over traditional chemotherapy in the treatment of non-Hodgkin lymphoma (NHL). Despite the potential of these agents, the delivery and release of cytotoxic agents to malignant cells through a combination of monoclonal antibody, payload, and linker represent a complex challenge. Nevertheless, because of recent innovations in the treatment of B-cell malignancies, the number of ADCs in clinical trials has increased in recent years. Moreover, these pipeline agents, such as polatuzumab vedotin, offer the potential to change the treatment landscape for NHL and other hematological malignancies through improved targeting and greater potency, compared with early-generation ADCs. This supplement reviews the development of ADCs, assesses the potential of investigational agents, and evaluates their role in the evolving treatment spectrum for lymphoma.

Overview of Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of lymphoid malignancies that originate in B cells, T cells, or natural killer cells and exhibit distinct clinical behavior and variable responses to treatments.1-3 NHL is the sixth most common cause of cancer death in the United States.4 In 2018, it is estimated that 74,680 new cases and 19,910 deaths due to NHL will occur in the United States.4 NHL is most prevalent in patients ≥70 years and in men.4

FL is the second most common form of NHL, comprising one-fifth of all NHL cases and accounting for up to 70% of the indolent lymphomas reported in clinical trials in the United States and Europe.3 Although FL usually follows an indolent course, it can lead to poor outcomes with relapse occurring within 2 years of initial treatment.6

Current Approaches to Therapy

Treatment of NHL is based on the patient's histologic subtype, extent of disease, and age.2 In addition, most chemotherapy agents target rapidly proliferating cancer cells nonspecifically, and they have toxic effects on normal tissue.7 Monoclonal antibodies, which usually offer inadequate clinical activity when used as monotherapy, are often used in conjunction with chemotherapy to treat lymphoma.7 First approved in the United States in 1997,10 rituximab is an anti-CD20 monoclonal antibody that has transformed the therapeutic landscape of B-cell malignancies, marking a paradigm shift with the beginning of targeted agents to treat lymphoma.7,10 Other monoclonal antibodies, such as obinutuzumab, a newer glycoengineered type II anti-CD20 monoclonal antibody, have also been incorporated into the treatment armamentarium for lymphoma.2


Figure 1. Critical Factors That Influence Antibody-Drug Conjugate Therapeutics.17

Figure 1. Critical Factors That Influence Antibody-Drug Conjugate Therapeutics.17

ADC indicates antibody–drug conjugate; DM1, DM4, derivatives of maytansine; MMAE, monomethyl auristatin E. Reprinted from Panowski S, Bhakta S, Raab H, Polakis P, et al. Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014;6(1):34-45.

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