Antibody Therapeutics – a primer

Consideration of antibodies as a therapeutic modality isn’t new. Ever since the discovery of anti-toxin antibodies and the observation of their efficacy against certain bacterial toxins (e.g. tetanus toxin) in the early 1890s, the subsequent 40-odd years saw a rise in the therapeutic usage of antibody preparations (under the umbrella term ‘serum therapy’) for various infectious diseases (N.B. informative reviews at References 1, 2 and 3) – the name indicating the origin of these preparations: polyclonal serum collected from immunized animals (such as sheep) or pre-exposed immune human donors. Serum therapy worked, no doubt, but also gave rise to various side effects related to the presence of a complex foreign protein substance (e.g. animal serum in a human body), a condition known as ‘serum sickness’, accompanied by fever, chills, joint pain, allergy, and in extreme cases, anaphylaxis. Although this challenge was somewhat resolved by the 1930s through better-purified antibodies, the introduction of vastly superior, potent, and better tolerated antimicrobial chemotherapy (‘antibiotics’, starting with sulphonamides and then the β-lactam, penicillin) around 1935 sounded the death-knell for serum therapy. Within 5 years, antibacterial serum therapy fell into disuse, leaving only a niche area for those conditions that were not amenable to antibiotic treatment, namely, venoms, toxins (such as diphtheria and tetanus), and viral infections (such as, hepatitis A and polio) (1).

However, to appropriate a popular saying, one “cannot keep a good antibody down“. Research into the principles, technology and use of antibody preparations hadn’t stopped. At the same time, there was an increasing appreciation of the fact that, although antimicrobials work (and work well) by slowing down and/or killing the microbial pathogens, the totality of host defence is a dynamic process dependent upon host-pathogen interactions – because of which immune therapies, including antibody-associated therapies, had a definite and important role to play in clinical therapeutics. In modern times, this realization has become even more crucial in view of three pathogen-related observations:

1. a notable increase in microbes resistant to specific antimicrobials (think of the antibiotic resistant bugs of recent times, such as methicillin resistant Staphylococcus aureus or MRSA),
2. the increased use of invasive diagnostic and therapeutic techniques, which – while beneficial – have paradoxically made a subset of the patient population more vulnerable to ubiquitous microbes (think of catheters and catheter-associated infections), and
3. a sharp increase in the patient subset with immune impairment, whether conditional (think of immune suppression prior to, say, organ transplant), metabolic (as in diabetes and certain cancers), genetic (such as ‘hypogammaglobulinemia’, a condition which results in very low levels of antibodies in the body), or disease-associated (as in HIV-infection and AIDS); in such patients, even otherwise-innocuous microbes can also cause disease.

Not surprisingly, this situation resulted in a renewed interest in immune-based therapies, including antibody therapy, aimed at combating disease by buttressing host immunity.

A historical example of antibody use is the intravenous immunoglobulin (IVIG) therapy developed in the 1980s; IVIG is a polyclonal antibody preparation derived from healthy donors (whose blood contains antibodies recognizing diphtheria toxin, measles and polio virus at the minimum, as a result of direct exposure, or vaccination) (2). It has been successfully used as replacement therapy in hypogammaglobulinemics, as well as prophylactically and therapeutically in many viral infections, such as hepatitis A and B, polio, rabies, measles, rubella (German measles), cytomegalovirus, and varicella (Chicken pox); IVIG is also indicated in immunosuppressed patients and newborns as therapy of acute infections, as well as post-exposure prophylaxis. In addition, polyclonal antibodies from hyperimmunized sheep, horses and rabbits are used as antidotes against envenomization (snake and spider venom), certain bacterial toxins (such as Clostridium botulinum neurotoxin), digitalis toxicity, as well as to cause immune suppression in organ transplant recipients to prevent rejection (3).

Given the unique characteristic of high antigen-specificity of Monoclonal Antibodies or MAb(s) (which I touched upon briefly in the previous post), it is expected that the practice of antibody therapeutics would embrace this technology. In fact, when Georges Köhler and César Milstein jointly described the technology in their seminal Nature paper in 1975 (Nature 256:495–497, 1975), MAbs were hailed as the ‘Magic Bullet’ that harnessed the therapeutic power of specific antibodies against specific diseases.

Unfortunately, the physiological system, in health and disease, is often too complex a system to be easily reduced to single components; it is truly greater than mere sum of its parts. A lack of appreciation of this in the early days of biology and medicine led to a lot of headaches. Thankfully, such is the nature of science, that from each such failure, as well as from the small measures of successes, scientists have learnt, reasoned, experimented and put that knowledge to good use.

Take, for example, serum sickness that I have mentioned above, which restricted the utility of serum therapy, especially in situations requiring prolonged use. Even purified polyclonal antibodies from animals, which have high specific activities, are not always immune from this shortcoming, especially on long-term use. Again, IVIG, made according to strict criteria, are in limited supply and have low capacity of recognizing specific antigen (which is not surprising, since they are pooled from healthy donors). MAbs offered a solution to some of these challenges, and became popular in biologic therapeutics; however, that is not to say that MAbs don’t have problems specific to their own (3).

The single-epitope specificity of MAbs is beneficial for targeted functions, such as (a) blocking of molecular interactions; and (b) targeting of specific components. The following is a (non-exhaustive) list of a few therapeutic MAbs currently approved by US FDA (4, 5, 6):

Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AS, ankylosing spondylitis; BAFF, B-cell activating factor; CAPS, Cryopyrin-associated periodic syndromes; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukemia; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic T lymphocyte antigen 4; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IL, interleukin; JIA, juvenile idiopathic arthritis; MS, multiple sclerosis; NHL, non-Hodgkin’s Lymphoma; R, receptor; RA, rheumatoid arthritis; RANK-L, receptor activator of NFkb ligand; RSV, respiratory syncytial virus; SLE, systemic lupus erythematosus; TNF,tumour necrosis factor; UC, ulcerative colitis; VEGF-A, vascular endothelial growth factor A.

In addition to above, certain MAbs have been used as targeting agents for specific delivery of a toxic payload to cancer cells; for example, (a) Ibritumomab tiuxetan and Tositumomab-I131 (both recognize CD20 on normal and malignant B-cells) are used in NHL to deliver a radioactive isotope (Yttrium-90, Indium-111, or Iodine-131) which kills B-cells, leaving the void to be filled by a fresh batch of healthy B-cells from bone marrow; (b) Brentuximab vedotin (anti-CD30 present on T- and B-cells) is used in Hodgkin’s lymphoma and anaplastic large cell lymphoma to deliver the anti-mitotic drug vedotin, which inhibits the proliferation of cancer cells.

I don’t know about you, but I am fascinated by the power of the MAb technology. However, the same characteristic of specificity may cause restricted functionality of the MAbs; they cannot bind to multiple epitopes, and therefore, are not very effective against complex epitopes (as in certain bacterial toxins), nor in situations in which there are too many targets (due to heterogeneous cell populations, as in many cancers) or the density/availability of targets are low (due to low target expression, as in certain tumors). A related but different problem arises because of low levels of targets present elsewhere in the body; binding of the MAb to those molecules outside of the target tissue may cause unintended toxicities and side effects (7), which has over time led to the withdrawal of certain approved MAbs from the market. In addition, having been made in vitro, MAb also fail when the targets change (mutate or evolve). This has been the single most important difficulty that has prevented generation of MAb therapeutics against infectious diseases, because pathogens often evolve to adapt to the host body.

A timeline of evolution of Antibody Therapeutics in the US:

In the totality of Antibody Therapeutics, MAbs have had several iterations of importance, which I shall discuss in the next post.

This is the SECOND PART of a multipart series on exciting new developments in the world of antibodies.