Monoclonal Antibody Therapies for Children

Monoclonal antibodies are produced by transformed cell lines, engineered to create antibodies with a uniform specificity. Because monoclonal antibodies are derived from a living source, they are designated as biologic medications and provided through specialty pharmacies able to facilitate the dispensing of these medications. The effectiveness of monoclonal antibody therapies is dependent on the ability of the antibody’s antigen-binding fragment (Fab) portion to target a specific epitope, typically neutralizing a key function of a protein by binding to it. Because monoclonal antibodies can neutralize a broad range of antigens, they have been used to neutralize infectious pathogens as well as target human proteins implicated in disease, including cancers, allergic disease, and autoimmune conditions.In addition to neutralizing the function of proteins through binding, the crystallizable fragment (Fc) region of antibodies can increase destruction of target cells by activating complement and by facilitating opsonization by phagocytes after binding. Additional mechanisms for destroying target cells include the addition of toxins to the monoclonal antibody and the use of “bispecific” antibodies that use 2 different Fab arms, useful for linking 2 targets together. Adjustments of the Fc portion of the antibody can also alter the stability, activity, and longevity of the medication.Once a monoclonal antibody is developed, it becomes easily scaled up in laboratories. This contrasts with polyclonal antibodies that are derived from whole organisms, such as humans immunized with rabies virus to produce the human rabies immunoglobulin products used for postexposure prophylaxis. The uniformity of the monoclonal antibody target is also useful for the potential to elicit a uniform response. The response varies by specific epitope binding on the target antigen, with minor changes making a clinically meaningful difference.There are currently 46 monoclonal antibody products labeled for use in children (Table 1). The first Food and Drug Administration (FDA) approval of a monoclonal antibody therapy was for muromonab in 1986, a mouse-derived antibody targeting the cluster of differentiation (CD) 3 complex on T cells to prevent transplant rejection. The only other mouse-derived monoclonal antibody approved by the FDA for use in children is isblinatumomab, a bispecific monoclonal antibody that targets both CD3 on T cells and CD19 on B cells, leading to T cell–initiated apoptosis of the B cell once both are bound. Mouse-derived proteins can elicit human immune responses. Therefore, most monoclonal antibodies used as medication include human DNA (DNA). Fully human antibodies are denoted with the suffix -umab. Monoclonal antibodies with the complementary-determining region of DNA derived from an animal model, spliced into DNA that otherwise encodes production of a human antibody, are called humanized monoclonal antibodies and denoted with the suffix -zumab. Monoclonal antibodies produced by human–mouse chimeric cells are denoted with the suffix -ximab. These are generally well tolerated; side effects that do occur are related to a specific drug. Because of this, familiarity with side effects an important consideration for physicians that prescribe monoclonal antibodies (Table 2).The most commonly used monoclonal antibodies in children are those that directly antagonize aberrant functioning of the immune system. Monoclonal antibody treatments for allergic disorders are generally very well tolerated. By targeting common pathways in atopic disease, these therapies often have multiple indications. For example, dupilumab, which targets the interleukin-4 receptor alpha, inhibits the activity of interleukin-4 and interleukin-13, interrupting a wide range of allergic processes. Dupilumab has indications for asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, atopic dermatitis, and prurigo nodularis. Omalizumab binds to the Fc portion of circulating IgE, thereby preventing its insertion into mast cells, basophils, and eosinophils. Omalizumab has indications for asthma, chronic urticaria, chronic rhinosinusitis with nasal polyposis, and food-induced anaphylaxis. As research progresses, the number of indications—as well as age range covered by those indications—is likely to increase.Monoclonal antibodies that neutralize infectious agents may target key proteins for cell entry (such as the F protein of respiratory syncytial virus), or they may be directed at epitopes of toxins that neutralize toxicity. In contrast to monoclonal antibodies directed against human proteins, the ongoing evolution of infectious agents means that antibodies that are initially effective may become less effective over time. This was seen in the variable effectiveness of monoclonal antibody therapies for severe acute respiratory syndrome coronavirus 2. The ability to rapidly develop monoclonal antibodies to neutralize pathogens during infectious outbreaks, such as Ebola virus, is an important public health capacity because the polyclonal antibody therapies derived from convalescent serum have not generally been effective.Monoclonal antibodies used in cancer therapies include treatments targeting entire groups of cells (eg, rituximab that eliminates both cancerous and noncancerous B cells). Monoclonal antibodies targeting specific oncogene products, such as human epidermal growth factor receptor 2, are more commonly used in adult patients. As with the evolution of pathogens, cancers also can evolve mechanisms to overcome the effectiveness of these treatments. Beyond targeting cancerous cells directly, an increasing number of checkpoint inhibitors have been developed. Immune checkpoints block immune responses; when appropriately invoked, immune checkpoints prevent immune activation against targets that are benign. However, the immune checkpoints also inhibit immune attacks against cancerous cells. Medications that inhibit checkpoints allow the immune system to attack cancerous cells.Most of the conventional medications used in treating autoimmune disorders have large effects on autoimmune T cells but relatively modest effects on autoreactive B cells. Monoclonal antibodies used to deplete B cells and other components of inflammation provide superior outcomes in comparison with traditional medications. However, these immunosuppressive therapies increase the risk of opportunistic infection; careful evaluation is needed before and during treatment. Immunologists increasingly comanage patients with severe autoimmune diseases who experience life-threatening infections while on therapy.Less commonly used monoclonal antibodies target proteins in specific medical conditions. For example, alirocumab targets the proprotein convertase subtilisin/kexin type 9 enzyme for patients with high cholesterol associated with heterozygous familial hypercholesterolemia, and pozelimab is used to treat CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy. The investment in research for developing medications for rare disorders, when spread among the lower number of patients who would benefit from it, can lead to prohibitive costs. There are substantial incentives for drug development for such “orphan diseases” that have been somewhat successful in prompting research on monoclonal antibody treatments.Challenges in using monoclonal antibody therapies include cost, difficulty in obtaining prior insurance coverage authorization, the need to partner with specialty pharmacies, and the many other barriers accessing health care that limit access of patients to physicians comfortable with their use. These medications are generally not thought to be disease modifying, and many patients are uncomfortable with the prospect of lifelong treatment. This is especially true because most monoclonal antibody therapies are administered through subcutaneous injections. Patients with public insurance and those identified as racial or ethnic minorities are less likely to be prescribed monoclonal antibodies for asthma management. This differential prescribing is likely also present for the less-common conditions for which monoclonal antibodies are being prescribed. There is a need for monitoring equitable use of these medications in populations that experience the greatest need.The small number of children with rare conditions makes trials with patients in the pediatric age range less attractive to companies weighing the cost of conducting studies with the potential return on that investment. Without explicit FDA approval for medications in a younger age group, insurance companies routinely deny coverage. A pediatric gastroenterologist in Louisiana successfully advocated for state law ensuring insurance coverage of medications lacking a label for children. This demonstrates that state-level advocacy is effective in gaining access to these medications for children.As the safety of using monoclonal antibodies has become clear, they are increasingly dispensed to patients for home use. Families gain comfort with using prefilled syringes and autoinjectors over time. When paired with telehealth visits to the subspecialists who prescribe these medications, the ability to dispense medications to families for home use holds promise for increasing access to this class of medication.Comment: I still vividly recall the first patient I witnessed being started on a monoclonal antibody for Crohn’s disease. I was a pediatric resident on a gastroenterology rotation, and the 15-year-old boy before me was thin and morose, his mother anxious and hyper-vigilant. The change after the boy’s first infliximab infusion was dramatic. When he and his mother came for follow-up, they raved about the almost complete elimination of all his symptoms; a weight was lifted off their shoulders. And yet, while modern medicine is amazing, it is rarely purely miraculous.Later during the rotation, I witnessed the utter disappointment of a family whose child was experiencing the lupus-like syndrome of joint pain, fatigue, and fever that can be associated with infliximab toxicity.With the recent FDA approval of nirsevimab to protect infants against RSV, I am excited again for the miracle-like possibilities of a monoclonal antibody. The safety profile of nirsevimab is highly reassuring, so nirsevimab has been recommended for all infants up to 8 months old in their first RSV season, as well as some highrisk infants 8–19 months old in their second RSV season.The first year after nirsevimab approval was plagued by drug shortages and unequal uptake among children. As we gradually see higher, more even coverage among all children, I am eagerly awaiting a winter season in which infants gasping for air in the “tripod position” is a rarity, not the norm, in urgent cares, emergency departments, and inpatient units.Linda Fu, MD, MSAssociate Editor, In Brief