All protein therapeutics are potentially immunogenic. Indeed, severe immune responses, including immediate hypersensitivity
responses and neutralizing antibody responses resulting in clinical sequelae, have brought the issue to light. Immediate hypersensitivity
responses can manifest as life-threatening anaphylactic reactions, and neutralizing antibody responses can not only neutralize
the therapeutic protein, but also its endogenous counterpart, leaving patients with a clinical deficiency syndrome. Yet, for
many therapeutic protein products the antibody response has little apparent effect. So how does FDA, with the myriad products
it regulates, approach immunogenicity concerns for novel products in development and for major changes in manufacture and
clinical use of licensed products? This brief review will focus on the scientific basis of the Agency's risk assessment strategy
for immunogenicity. There will be two other parts to the discussion. Next month we will cover two more elements, and the final
month will cover effects of manufacturing changes on immunogenicity.
RISK ASSESSMENT STRATEGY
First Element: Consider the severity of consequences of the immune response to a protein therapeutic.
Critical Factors: The origin of the product and the presence and biological function of endogenous protein counterparts.
When considering immune responses engendered by therapeutic proteins, the paramount concerns are safety and efficacy. The
latter consideration is particularly prominent when immune responses abrogate efficacy of lifesaving therapies. FDA views
these safety and efficacy concerns hierarchically.
Product Origin: Xenobiotic products
Consequences: Hypersensitivity responses and neutralizing antibody development
The most serious types of immune responses are immediate hypersensitivity reactions, especially when severe. Such responses,
though relatively rare, are most frequently associated with xenobiotic products including microbial products (for example,
streptokinase,1 asparaginase,2 urate oxidase,3 and toxin conjugates) and animal proteins (murine or chimeric MAbs4 and aprotinin5), but they also occur with some human origin products. The incidence typically rises on re-exposure, but the time lapse between
exposures may critically alter incidence. For example, there is a 5% incidence of anaphylaxis upon re-exposure to aprotinin
within six months but a much lower incidence following a greater time interval.5
The development of neutralizing antibody is expected with administration of foreign proteins, limiting product efficacy. However,
the rapidity of development or strength of the immune response may be modified to some degree via alteration of key product
attributes such as product aggregates, adjuvants, and glycosylation state. Pegylation also has been employed to thwart immune
FDA Recommendation. Because immediate hypersensitivity responses cannot be predicted from product characteristics, patient-associated factors,
or animal studies, treatment with such products may require skin prick testing prior to initial administration2 and treatment should be administered in a setting where life-threatening events can be remediated. Moreover, in recurrent
administration, where the risk of hypersensitivity responses increases, testing for IgE generation by radioallergosorbent
test (RAST) assay and skin prick tests before continued dosing may be warranted to reduce the incidence of catastrophic responses.
Product Origin: Human sequence; mammalian cell substrate
Consequences: Antibodies that neutralize both therapeutic and endogenous proteins; hypersensitivity responses
Hypersensitivity responses are infrequent with human-origin protein products, particularly in patients with a fully functional
endogenous protein counterpart to the therapeutic, but they occur to a variable extent when the endogenous protein counterpart
is mutated and nonfunctional or absent due to deletion mutations.
Generation of neutralizing antibody to a therapeutic protein product is deleterious if it blocks the therapeutic efficacy
of the product, but it can be devastating when it cross-reacts on an endogenous protein counterpart of the therapeutic. Why
is it possible to break tolerance to a normal endogenous protein and neutralize its activity? The answer is that immunological
tolerance to endogenous soluble proteins is not complete for proteins present at low levels: T and B cells specific for low-abundance
autoantigens are not completely eliminated from the body and, given sufficient provocation, can generate immune responses.7 This is the basis for autoimmune responses and, potentially, for fail-safe mechanisms for potent cytokines and growth factors.8,9