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On-Target and Off-Target Effects (Immunogenicity) Can Be Possible Safety Concerns


The Choice of Target Impacts the Potential for Immune-Related and Target-Related Effects

mAbs that modulate the immune system can result in immune-related toxicities. mAbs that do not target the immune system are not usually associated with immune-related toxicities, although they can result in other target-related toxicities.

Inflammatory Diseases1

For example, specific mAbs have been developed that deplete immune cells that express CD20, reducing inflammation.

Depletion of immune cells, such as those expressing CD20, by mAbs can increase the risk of opportunistic infections.

Cancer2

For example, specific mAbs have been developed that target VEGF, inhibiting angiogenesis and reducing tumor growth.

Inhibition of VEGF by mAbs may reduce growth of new blood vessels in healthy tissues, leading to GI perforations and complications in wound healing.

GI, gastrointestinal; mAb, monoclonal antibody; VEGF, vascular endothelial growth factor. 1. Kelesidis T, et al. Int J Infect Dis. 2011;15:e2-e16. 2. Tabrizi MA, et al. Drug Discov Today. 2007;12:540-547.
mAbs &
small molecules
Antibody-based
therapeutics

Summary of Differences Between mAbs and Small Molecules1

PropertySmall molecule mAb
Size~500 daltons~150,000 daltons
SpecificityLowerHigh
MetabolismHepatic/RenalReticuloendothelial system,
target-mediated disposition
ToxicityBroken down into chemical metabolites;
often cleared by liver or kidneys
On-target (depends on the target of the mAb)
and off-target toxicities (eg, immunogenicity)
Drug-drug interactionsMore likelyLess likely
Crossing blood-brain barrier2Potentially yes*Minimal
AdministrationUsually oralIntramuscular, subcutaneous,
or intravenous
Half-life3~HoursDays to weeks
DosingUsually dailyTypically less frequent (eg, monthly)
Production4,5Chemical synthesis; relatively easy
to make and reproduce reliably
Produced inside unique line of modified living
cells; difficult to make and reproduce precisely

*Depending on degree of lipid solubility.

mAb, monoclonal antibody.
1. Foltz IN, et al. Circulation. 2013;127:2222-2230. 2. Tabrizi M, et al. AAPS J. 2010;12:33-43. 3. Silberstein S, et al. Headache. 2015;55:1171-1182. 4. Kleinberg M, et al. Am J Health
Syst Pharm. 2004;61:695-710. 5. Committee on Methods of Producing Monoclonal Antibodies. Monoclonal Antibody Production. 1999.

Antibody-Based Therapeutics

Research and Development of mAbs Is Rapidly Evolving

The First mAb Was Produced in 1975; Since Then1

mAb, monoclonal antibody.
1. Silberstein S, et al. Headache. 2015;55:1171-1182. 2. Cai HH. MOJ Immunology. 2017;5:145. 3. Foltz IN, et al. Circulation. 2013;127:2222-2230.