Tumours: Targeting of Monoclonal Antibodies for Imaging and Potential for Therapy

Abstract

Antibodies by virtue of their unmatched specificity and diverse modes of action are the central components of the immune system to detect and combat pathogenic and nonpathogenic diseases. From the era of polyclonal antibodies to fully humanised monoclonal antibodies, a lot has been understood regarding their causal generation, molecular buildup, varied functioning and clearance from the biological system. This information has led to their widespread use in various arenas of pathogenesis including parasitic, bacterial and viral infections, heart diseases, autoimmune diseases and cancer. Since cancer derives from self, it is both difficult to diagnose as well as treat. With over 20 antibody‐based drugs now in use and over 100 in clinical trials for cancer, antibodies form the basis of several diagnostic as well as therapeutic modalities for some lethal malignancies. Further, antibody engineering to improve their characteristics, such as pharmacokinetics, has made them a major attraction for the biopharmaceutical industry.

Key Concepts:

  • The efficacy of murine monoclonal antibodies is limited by the inefficient action of the murine‐derived constant region and human anti‐mouse antibody response, resulting in their rapid clearance from the blood.

  • The success of an antibody‐based biopharmaceutical depends upon target antigen (location, distribution and density), targeted site (solid or haematological malignancy, tumour microenvironment) and targeting antibody (specificity, affinity, avidity, mode of action, origin and isotype).

  • Antitumour antibodies mediate their effector functions by antibody‐dependent cellular cytotoxicity, complement‐dependent cytotoxicity and antibody‐dependent cellular phagocytosis.

  • Antigenic heterogeneity, lack of tumour specificity, immunogenicity and nonuniform distribution of antibodies to the targeted site are major hurdles in successful use of antibody‐based therapeutics for solid tumours.

  • Antibodies against molecules inhibiting effector functions of helper and cytotoxic T cells improve the efficacy of an antitumour immune response.

  • Antibodies directed against co‐stimulatory receptors act as surrogate ligands and boost weak, ineffectual and endogenous antitumour immune responses.

Keywords: tumour targeting; antibodies; imaging; monoclonal; immunoscintigraphy

Figure 1.

A schematic representation of various factors regulating antibody‐mediated oncological imaging. The successful imaging of tumour lesion is multi‐factorial event and dependent upon several factors. (a) Imaging modality: The type, resolution, sensitivity, ability to discriminate tumour lesion from overlaying structures and its compatibility with other modalities; (b) Radionuclide and targeting agent: (i) The half‐life, toxicity, nature of particle emitted by radionuclide (alpha‐, beta‐ gamma and auger) along with method used for its conjugation with targeting agent and (ii) size, stability, specificity, affinity, clearance kinetics, tumour penetrance ability of targeting agent (antibody); and (c) Host: Physiology of the host, including (i) location, specificity, distribution and density of antigen and (ii) location, vascularisation, and microenvironment of targeted organ. Overall, constrains associated with imaging modalities and/or host have been addressed through generation and modification of various antibodies and antibody fragments (intact antibody, monomeric, dimeric, Fab and F(ab’)2), via antibody engineering, advancement in imaging modalities and development of better conjugation chemistries for antibody–radionuclide complexes.

Figure 2.

(a) Nude mouse bearing a 1.6‐g human colonic carcinoma xenograft with the corresponding whole body scan, obtained 3 days after injection of 131I‐labelled immunoadsorbent, purified, intact, polyclonal goat anti‐carcinoembryonic antigen (CEA) antibodies (Mach et al., ). (b) Nude mouse with a similar xenograft of 0.1 g and the corresponding whole body scan taken 1 day after injection of 131I‐labelled Fab fragments from monoclonal anti‐CEA antibody 35. Reproduced with the permission of the Journal of Experimental Medicine (Buchegger et al., ), copyright: The Rockefellar University Press.

Figure 3.

Various antibody‐based therapeutics (humanised, chimeric and antibody–drug conjugates) approved for clinical use. Acute myeloid leukaemia, AML; epidermal growth factor receptor, EGFR; non‐Hodgkin lymphoma, NHL; colorectal cancer, CRC; vascular endothelial growth factor receptor, VEGF.

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Further Reading

Brennan DJ, O'Connor DP, Rexhepaj E, Ponten F and Gallagher WM (2010) Antibody‐based proteomics: fast‐tracking molecular diagnostics in oncology. Nature Reviews Cancer 10(9): 605–617.

Mellman I, Coukos G and Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378): 480–489.

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Kaur, Sukhwinder, Jain, Maneesh, Senapati, Shantibhushan, and Batra, Surinder K(Oct 2012) Tumours: Targeting of Monoclonal Antibodies for Imaging and Potential for Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001428.pub2]