Antibody-drug conjugates for lymphoma patients: preclinical and clinical evidences

Abstract

Antibody-drug conjugates (ADCs) are a recent, revolutionary approach for malignancies treatment, designed to provide superior efficacy and specific targeting of tumor cells, compared to systemic cytotoxic chemotherapy. Their structure combines highly potent anti-cancer drugs (payloads or warheads) and monoclonal antibodies (Abs), specific for a tumor-associated antigen, via a chemical linker. Because the sensitive targeting capabilities of monoclonal Abs allow the direct delivery of cytotoxic payloads to tumor cells, these agents leave healthy cells unharmed, reducing toxicity. Different ADCs have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of a wide range of malignant conditions, both as monotherapy and in combination with chemotherapy, including for lymphoma patients. Over 100 ADCs are under preclinical and clinical investigation worldwide. This paper provides an overview of approved and promising ADCs in clinical development for the treatment of lymphoma. Each component of the ADC design, their mechanism of action, and the highlights of their clinical development progress are discussed.

Assessment of lisavanbulin (BAL101553) as an anti-lymphoma agent

“…Moreover, since the avanbulin tubulin binding site differs from both vinca alkaloids and MMAE and it does not appear to be a MDR1 substrate 5,7,9,12,14 , lisavanbulin might be an alternative strategy also in patients that have developed resistance to these agents via tubulin mutations or MDR1 overexpression. A matter of concern for treating these patients is the potential overlapping toxicities, especially peripheral neuropathies, common to all MTAs 5,8,16–18 , which might represent a limiting factor for using lisavanbulin in individuals already exposed to vincristine, vinblastine or antibody drug conjugates containing a MTA as payload.…”

“…Due to their central role in cellular processes, including cellular division, microtubules still represent one of the main targets for anti-cancer therapy [5][6][7] . In the lymphoma field, successful examples of microtubule-targeted agents (MTAs) are vincristine and vinblastine, part of the R-CHOP and ABVD regimens, respectively, and monomethylauristatin E (MMAE), which is the payload in both brentuximab vedotin and polatuzumab vedotin 5,8 . Avanbulin (BAL27862) is an MTA characterized by the ability to bind to the colchicine site of tubulin, differently from other MTAs 9 .…”

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

“…As of 2023, three ADCs have received FDA approval for various types of lymphomas, which are Brentuximab Vedotin (BV), Polatuzumab Vedotin (PV), and Loncastuximab Tesirine (LT) [63], as shown in Table 1.…”

Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach

“…Despite the clear improvements achieved in the cure of patients affected by lymphoid neoplasms, novel therapeutic strategies are still needed since current therapies are not yet curative for too many persons (1)(2)(3). Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last 25 years (4)(5)(6). ADCs are complex compounds that contain three components: an antibody, a warhead (i.e., a cytotoxic agent) and a linker that joins the two together.…”

“…ADCs enable targeted delivery of potent warheads into tumor cell using antibodies specific for tumor antigens. Due to its pattern of expression and its biologic role in lymphocytes, the B cell marker CD19 has been heavily exploited for antibody-based therapies, including ADCs, and, more recently, for cellular therapies (5,(7)(8)(9)(10)(11)(12)(13)(14). Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the CD19specific antibody is stochastically conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199) (10).…”