Advances in the treatment of hematologic malignancies using immunoconjugates

Abstract

Monoclonal antibody therapy has revolutionized cancer treatment by significantly improving patient survival both in solid tumors and hematologic malignancies. Recent technological advances have increased the effectiveness of immunotherapy leading to its broader application in diverse treatment settings. Immunoconjugates (ICs) consist of a cytotoxic effector covalently linked to a monoclonal antibody that enables the targeted delivery of its therapeutic payload to tumors based on cell-surface receptor recognition. ICs are classified into 3 groups based on their effector type: immunotoxins (protein toxin), radioimmunoconjugates (radionuclide), and antibody drug conjugates (small-molecule drug). Optimization of each individual component of an IC (antibody, linker, and effector) is essential for therapeutic efficacy. Clinical trials have been conducted to investigate the effectiveness of ICs in hematologic malignancies both as monotherapy and in multiagent regimens in relapsed/refractory disease as well as frontline settings. These studies have yielded encouraging results particularly in lymphoma. ICs comprise an exciting group of therapeutics that promise to play an increasingly important role in the management of hematologic malignancies.

Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody–Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies

“…Brentuximab vedotin received accelerated approval by the FDA in 2011 and conditional approval in Europe in 2012 for patients with relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma (8,9). Other ADCs are in development based on the same linker/drug technology, including polatuzumab vedotin and pinatuzumab vedotin (targeting CD79b and CD22, respectively), both of which are in phase II development for the treatment of diffuse large B-cell lymphoma and follicular lymphoma (10). Ado-trastuzumab emtansine is composed of the anti-HER2 antibody trastuzumab connected via a stable thioether linker to the potent antimicrotubule agent derivative of maytansine 1, an inhibitor of microtubule dimerization (11,12).…”

“…GCC is expressed in 60% to 70% of pancreatic, gastric, and esophageal cancers (19)(20)(21) and 95% of primary and metastatic colorectal cancer (16,18,(22)(23)(24). Systemically delivered GCC-targeting agents are expected to be preferentially delivered to GCC receptors in tumor tissue, while leaving normal tissues unaffected, as GCC is expressed on the apical side of epithelial tight junctions (10,16,23,25,26). Access to GCC receptors is enabled in tumor tissues as a result of disrupted cell polarity, altered tight junction architecture, and disruption of its apical localization (16,18,22,24).…”

Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity

“…89 Finally, multiple antibody drug conjugates targeting B-cell surface markers are being evaluated. 132 As an example, polatuzumab vedotin, an antibody drug conjugate targeting CD79B that is universally expressed in DLBCL, has induced response rates in 48% of patients with relapsed/refractory DLBCL in a phase 2 trial and is undergoing evaluation in combination trials. 133 Despite this plethora of emerging therapies, the practical challenges of making further progress in DLBCL remain formidable.…”

Structure-based design and synthesis of a bivalent iminobiotin analog showing strong affinity toward a low immunogenic streptavidin mutant

“…One possible use is in a pre-targeting system, conjugated with a monoclonal antibody. [7][8][9][10][11][12][13][14][15] In this pre-targeting application, a monoclonal antibody-SA conjugate is first injected into a patient and allowed to localize at the tumor. The excess reagent is then cleared and the biotinylated radiation carriers are administered.…”