Investigational Antibody–Drug Conjugates for Treatment of B-lineage Malignancies

Abstract

Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated.

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

“…The results of our investigation show that pola-related analytes have generally similar plasma/serum PK when given in combination with rituximab-and obinutuzumab-containing therapies, and between patients with mixed subtypes of B-NHL or DLBCL, and between treatment-naïve versus R/R status. Based on the range of geometric means across treatment arms in study GO29044, acMMAE was characterized by a V ss mostly restricted to the central compartment (57.3-95.6 mL/kg), including a low CL (12.7-18.2 mL/kg/ day) and long t 1/2 (4.75-5.45 days), which is consistent with prior knowledge [14,15]. Moderately higher acMMAE concentrations were seen in subsequent cycles with q3w dosing relative to cycle 1, which indicated accumulation, potentially due to time-dependent decrease of clearance of acMMAE (unpublished data on file).…”

“…After internalization, the linker is cleaved, resulting in the intracellular release of MMAE, which binds to tubulin to inhibit polymerization triggering tumor cell death [11]. Pola has demonstrated promising activity with combination agents in several clinical trials in patients with B-NHL and continues to be investigated in a phase III clinical trial [13][14][15][16][17][18]. Combining pola with rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) has a manageable safety profile and promising preliminary clinical activity in newly diagnosed DLBCL [19], supporting the initiation of a phase III trial comparing pola + R-CHP to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).…”

BCMA-targeted immunotherapy for multiple myeloma

“…Early studies on anti-BCMA antibodies showed robust cytotoxic activity against MM cells in vitro [68]. Currently, multiple innovative BCMA-targeted treatment modalities, including antibody-drug conjugate (ADC), CAR-T cells, and bispecific T cell engager (BiTE), are under active clinical development [13,14,[69][70][71][72][73][74][75][76][77] (Fig. 3).…”

Differential Expression of CD43, CD81, and CD200 in Classic Versus Variant Hairy Cell Leukemia

“…However, from a treatment standpoint, therapeutic modalities targeting CD79b may potentially be applicable to all cases of HCL and most cases of HCLv. Two examples of CD79b-targeted therapy, Polatuzumab vedotin, and Iladatuzumab vedotin (DCDS0780A), are antibody-drug conjugates comprised of an anti-CD79b CD43, CD81, AND CD200 IN HCL AND HCLV antibody linked to monomethylauristatin E, and are currently under investigation in clinical trials for potential therapeutic utility in B-cell malignancies (50). CD200 (OX-2) is an immunoglobulin superfamily membrane glycoprotein that is expressed by various cell types including B-cells, thymocytes, activated T-cells, and neuronal and endothelial cells.…”