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

Immunogenicity Involves Production of Non-Neutralizing and/or Neutralizing Anti-Antibodies1,2

Antibodies may be formed against the therapeutic mAb (also known as immunogenicity). Although these “anti-antibodies” may not always have an apparent effect, they may alter mAb pharmacokinetics, reduce mAb efficacy, or lead to the development of adverse events (eg, hypersensitivity or anaphylaxis). These are rare in human mAbs compared with mAbs containing mouse sequence.

Non-Neutralizing Anti-Antibody

A non-neutralizing anti-antibody binds to a region of the mAb that does not block its ability to bind antigen; this may alter pharmacokinetics.

Neutralizing Anti-Antibody

A neutralizing anti-antibody recognizes and binds to the antigen-binding site of the therapeutic mAb, thus inhibiting the ability of the mAb to bind its target, which may impact its efficacy.

mAb, monoclonal antibody.1. Silberstein S, et al. Headache. 2015;55:1171-1182. 2. Carrascosa JM. Actas Dermosifiliogr. 2013;104:471-479.
mAbs &
small molecules

Summary of Differences Between mAbs and Small Molecules1

PropertySmall molecule mAb
Size~500 daltons~150,000 daltons
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.