Table 1.
Summary of data for targeting ligands
| Ligand | Target molecule (cell) | KD (nM) | MR kDa size (nm) | Immunogenicity | Clinical status | Costs of production | References |
|---|---|---|---|---|---|---|---|
| Antibody fragments | |||||||
| Fab | eg, NCA-90 (granulocyte), CEA (apical surface of gastrointestinal epithelium, lung tissues, breast, and colorectal cancer), VEGF (breast, colon, lung, gastric, renal, and oropharyngeal cancers), HER2 (breast, ovarian, stomach cancer) | 0.037–1 | 50 (5) | Lower than mAb | Approved by FDA: certolizumab pegol, CEA-scan | $615/40 mg | 59,170–174 |
| scFv | eg, CEA, HER2 | 0.018–1.1 | 30 (3) | Lower than Fab | Preclinical trials | Low | 170,171 |
| Monoclonal antibodies (mAb) | |||||||
| Rituximab | CD20 (pre-B and B-cell) | 8 | 145 (15) | * | In clinical use | High cost of final product, about $2,000–$20,000/g | 53,175,176 |
| Trastuzumab | HER2 | 5 | 145 (15) | ** | 50,53,177 | ||
| Bevacizumab | VEGF | 0.5 | 145 (15) | *** | 53,172,175,178 | ||
| Alemtuzumab | CD52 (lymphocytes, especially T-cells, monocytes, macrophages, monocyte-derived dendritic cells [moDCs], and the epithelial cells of the distal epididymis) | 0.1 | 145 (15) | **** | 179,180 | ||
| Panitumumab | EGFR (normal cells and non-small-cell lung cancer [NSCLC], breast, head and neck [squamous cell carcinoma of head and neck], gastric, colorectal, prostate, bladder, pancreatic, ovarian, and renal cancers) | 0.05 | 145 (15) | • | In clinical use | High cost: $2,000–$20,000/g | 17,42 |
| Proteins and peptides | |||||||
| RGD | Integrins αVβ3 and αVβ5 (overexpressed on tumor endothelium) | 3.2–100 | 1–5 (1–2) | High | Clinical trials | Low | 87 |
| DARPins | eg, CD4 (T helper cells, monocytes, macrophages, and dendritic cells), HER2 | pM–nM Av 4–10 nM | 14–20 (5–10) | High | Phase I/II clinical trials | Low | 97,100 |
| DNA or RNA oligonucleotides | |||||||
| Aptamers | proteins, surface receptors | μM–pM Av< 1 nM | 8–13 (3–5) | Low | FDA approved: Macugen | Low | 106,181–184 |
| Other targeting molecules | |||||||
| Folates | folate receptors: RFC (all cells), FR (ovarian, brain, head and neck, renal, and breast cancers) | 1–300 | 0.44 (0.3) | Low | Yes | Low | 114,118,120 |
| Lectins | Lectins receptor: DC-SIGN (dendritic cell), CLR (cancer) | μM | 10–200 (2–20) | · | Not in clinical use | low | 130,185 |
| Transferrin | CD71 (present on all cells, but overexpressed on cancer cells) | 1–10 | 80 (5–10) | Low | Not in clinical use | Low | 132,133,186 |
Notes: Size–length in the longitudinal section;
low: 11% positive in HACA test;
very low: 0.11% positive in HAHA (human anti-human antibody) test (Genentech, Inc., South San Francisco, CA, USA);
very low: 0.63% tested patients positive for treatment-emergent anti-bevacizumab antibodies;
anti-alemtuzumab antibodies were detected in 80.2% of alemtuzumab-treated patients. Titers generally increased during first 3 months of each course, declined by month 12. At month 12, 29.3% of patients remained positive for anti-alemtuzumab antibodies; ·low: 2% patients developed binding and neutralizing antibodies;
some are potent toxins. Costs are in US$.
Abbreviations: Av, average; CEA, carcino-embryonic antigen; CLR, C-type lectin receptor; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; EGFR, endothelial growth factor receptor; FR, folate receptor; Fv, variable fragments; Fab, antigen-binding fragments; KD, equilibrium dissociation constant; MR, mannose receptor; RFC, reduced folic carrier; mAbs, monoclonal antibodies; scFv, single chain variable fragments; VEGF, vascular endothelial growth factor.