Site-specific antibody drug conjugates for cancer therapy

Abstract

Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors—target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0–8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…Indeed, certain antibody-drug conjugates (ADCs) [11][12][13][14] and small molecule-drug conjugates (SMDCs) [2] have exhibited promising activity in preclinical models of cancer. Recently, two ADC products (Adcetris™ and Kadcyla™) have gained marketing authorization for oncological applications.…”

“…It has generally been assumed that ADC and SMDC products would crucially rely on the use of ligands, capable of selective internalization of the conjugate into the tumor cells, followed by an intracellular liberation of the cytotoxic payload [11][12][13][14]. This concept, however, has recently been challenged, as potent and selective anticancer activity has been observed with ADCs and SMDCs specific to antigens, which do not internalize [19,20,[28][29][30][31].…”

Pharmacological profile of a bifunctional ligand of the formyl peptide receptor1 fused to the myc epitope

“…In view of the increasing availability of therapeutic monoclonal antibodies that carry cytotoxic cargoes for anti-cancer therapy [11] or other conjugates supporting diagnostic procedures, we studied the feasibility of forcing intact cells to internalize known monoclonal antibodies by exploiting agonist-induced endocytosis of the FPR 1 triggered by a novel bifunctional agonist.…”

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

“…Thus, the 40-86 lysine residues on the antibody surface are modified to a variable degree, resulting in a sample with potentially 4.5 million different molecules in terms of regioisomerism and drug load 45,46 . If thiol-maleimide coupling is used instead, cysteine conjugation occurs after mild reduction of the four inter-chain disulfide bonds in the hinge region of an IgG1.…”