Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors.
Whereas over 85% of human cancers are solid tumors, of the 8 monoclonal antibodies (mAbs) currently approved for cancer therapy, 25% are directed at solid tumor surface antigens (Ags). This shortfall may be due to barriers to achieving adequate exposure in solid tumors. Advancements in tumor biology, protein engineering, and theoretical modeling of macromolecular transport are currently enabling identification of critical physical properties for antitumor Abs. It is now possible to structurally modify Abs or even replace full Abs with a plethora of Ab constructs. These constructs include Fab and Fab'(2) fragments, scFvs, multivalent scFvs (e.g., diabodies and tribodies), minibodies (e.g., scFv-CH3 dimers), bispecific Abs, and camel variable functional heavy chain domains. The purpose of the article is to provide investigators with a conceptual framework for exploiting the recent scientific advancements. The focus is on 2 properties that govern tumor exposure: 1) physical properties that enable penetration of and retention by tumors, and 2) favorable plasma pharmacokinetics. It is demonstrated that manipulating molecular size, charge, valence, and binding affinity can optimize these properties. These manipulations hold the key to promoting tumor exposure and to ultimately creating successful Ab therapies for solid tumors.
Beckman
Robert A
RA
Clinical Hematology-Oncology, Centocor Research and Development, Inc., Malvern, Pennsylvania 19355, USA. eniac1@snip.net
Weiner
Louis M
LM
Davis
Hugh M
HM
D000906:Antibodies / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods* / Q000639:trends
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007140:Immunoglobulin Fab Fragments