Glycans as Targets for Therapeutic Antitumor Antibodies

Abstract

Glycans represent a vast class of molecules that modify either proteins or lipids. They exert and regulate important and complex functions in both normal and cancer cell metabolism. As such, the most immunogenic glycans have been targeted in passive and active immunotherapy in human cancer for the past 25 years but it is only recently that techniques have become available to uncover novel glycan targets. The main focus of this review article is to highlight why and how monoclonal antibodies (mAbs) recognizing glycans, and in particular the glycans expressed on glycolipids, are being used in various strategies to target and kill cancer cells. The article reports on the historical use of mAbs and on very recent progress made in antitumor therapy using the anti-GD2 mAb and the antiganglioside mAbs, anti-N-glycolylneuraminic acid mAb and anti-Lewis mAb. Anti-GD2 is showing great promise in Phase III clinical trials in adjuvant treatment of neuroblastoma. Racotumomab, an anti-idiotypic mAb mimicking N-glycolylneuraminic acid-containing gangliosides, is currently being tested in a randomized, controlled Phase II/III clinical trial. This article also presents various strategies used by different groups to develop mAbs against these naturally poorly immunogenic glycans.

Carbohydrate Sequence of the Prostate Cancer-associated Antigen F77 Assigned by a Mucin O-Glycome Designer Array

“…The marked differences in carbohydrate antigen expression on cancer cells compared with normal counterparts have been discussed and reviewed extensively elsewhere (1–4). These arise from diverse changes in carbohydrate chains, including incomplete biosynthesis with loss of capping motifs, exposure of underlying backbones and cores regions, abnormal elongation and branching of backbone regions, inappropriate capping by sialylation, or alterations in sulfation and neo synthesis of sequences or overexpression of sequences that are normally minor components for particular cell types (35).…”

“…Among such long sought biomarkers are altered carbohydrates of cell surface glycoproteins and glycolipids on malignant cells (1–4). The murine mAb F77, IgG3 subtype, was raised against the prostate cancer cell line PC3 (5, 6) and found to recognize both androgen-independent (PC3, PC3-MM2, and DU 145) and androgen-dependent (LNCaP) human prostate cancer cells, with little or no binding to nonprostatic cells.…”

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“…Many of these “anti-cancer” antibodies turned out to be specific for different Lewis antigens. 33-36 Unfortunately, the development of these antibodies into anti-cancer therapeutics has been quite challenging, because many Lewis antigens are also expressed in several types of normal tissues, particularly in the mucosa of human gastrointestinal tract in the form of O -linked glycans attached to the mucins. 37-48 For example, anti-Le y antibodies showed strong side effects including nausea and vomiting in Phase 1 clinical studies because the expression of Le y in the gastrointestinal tract 33 …”

Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Antitumor Activity

“…Only a limited number of mAbs recognizing glycans have been described (13,14). GNX-8 (human IgG1) bound the extended type I chain epitope Le b -Le a (15) and FC-215 (murine IgM), an anti-Le x mAb that induced transient antitumor responses, but caused profound neutropenia in phase I trials (16,17).…”