Eli Lilly and Company (LLY) Earnings Call Transcript & Summary

Welcome to the immunogenicity session of the World Antibody Congress. My name is Jack Ragheb. Today, I will be speaking to you about antidrug antibodies and how they have impacted the development of monoclonal antibodies. Diphtheria antitoxin was the first biotherapeutic that was -- it was introduced in 1891, and this really marked the ushering in of the modern biotherapeutic area. Emil von Behring was the discoverer and developer of anti -- of diphtheria antitoxin, for which he won the very first Nobel Prize in Medicine in 1901. Diphtheria antitoxin had a major public health impact at the turn of the century. Shown here is diphtheria mortality for 100,000 in 23 American cities between 1885 and 1923, during which time the mortality rate dropped by nearly 90%, as the use of the antitoxin became more widespread. Much as today we are occupied with the COVID-19 pandemic, Americans of that time were equally occupied with the diphtheria pandemic and the therapies that were being developed to treat it. Here is a headline from a newspaper depicting the delivery of diphtheria antitoxin to Nome, Alaska during an outbreak in the city at a time when the blizzard had cut off all transportation in and out of Nome except by dog sled. This event actually had been memorialized in the annual Iditarod Dog Sled Race, which many of you have probably heard of, which occurs each year and retraces the steps of the trail of that dog sled team from Anchorage to Nome, Alaska over nearly 1,000-mile route. And for those of you who have children of a certain age, you may know the story from the major animated motion picture, Balto, which recounts the life and times of the lead dog in that sled team. So at that time, antitoxin was developed by immunizing large animals. And you can see in this photograph in the left that a horse is being bled to obtain its hyperimmune diphtheria antitoxin serum, but this was also performed with horses and sheep as well. And initially, whole serum was administrated, but for reasons that you will see, this also ushered in the era of more modern biopharmaceutical development by introducing ammonium sulfate precipitation of antibodies from sera and even pepsin cleavage. The story of diphtheria antitoxin is also notable for several other reasons. Some of the first large clinical trials were performed with diphtheria antitoxin in 1893. And unfortunately, due to fatal severe adverse events due to adulterated product led to the passage of the Biologics Control Act of 1902 and 1906, establishing what is now the FDA and regulation of all drug products. Despite the tremendous benefits of diphtheria antitoxin, there were also some rather serious adverse events associated with its use. And patients administered serum fairly uniformly develop fever; this very characteristic annular lesion called urticaria multiforme that you can see on the arms; the snake-like rashes on the palms of the hands and the soles of the feet; joint swelling, as you see here, you may be able to make out how this knee is swollen adjacent to this area of rash; swelling of the lymph nodes, not shown here; and kidney disease, also not depicted here, which could be life threatening or fatal. Clemens von Pirquet, pictured here, was the first to recognize this constellation of signs and symptoms associated with the use of diphtheria antitoxin. And he described these in a publication titled Serum Sickness, which is the term that he coined to describe these manifestations. And he also recognized that the cause of serum sickness was the development of human antibodies to the administered diphtheria antitoxin. And this was such a remarkable and radical concept that he wrote, and I've quoted here below his picture, "the conception that antibodies, which should protect against disease, are also responsible for disease, sounds at first absurd." Von Pirquet also described the primary and secondary anti -- so-called antidrug antibody response to the administered antitoxin and the specificity of the response. He also described what we call -- now call the prozone effect and recognized that the development of immune complexes and the manifestations of such occurs only when the antibody and the antigen are prevalent -- or excuse me, are present in the equivalence zone. Leapfrog about 100 years to 1985,and we have the introduction of the first therapeutic monoclonal antibody, Orthoclone OKT3. This antibody, while a recombinant monoclonal, was like diphtheria antitoxin, not of human origin, and in the case of OKT3, it was a fully mouse antibody. And as such, it was -- its use was associated with significant immunogenicity, immune complex disease and fatal anaphylaxis. The antibodies that arose to diphtheria antitoxin and to OKT3 were really directed against the nonhuman foreign sequences within the therapeutic antibody. And as monoclonal antibody technology advanced, murine sequences were minimized in an effort to reduce immunogenicity and reduce these associated adverse events. First were chimeric antibodies, in which the constant region of the mouse, shown in pink, were replaced by human sequences. And subsequently, humanized antibodies such that the only portions of the original mouse antibody that were retained in the therapeutic were the CDR3 regions and some framework sequences that were necessary to maintain their confirmation. The first humanized antibody was daclizumab, and as nicely depicted in the space-filling model with the mouse sequences, shown in red, one can easily see the residual CDR3 sequences present in the humanized antibody. Humanization of this antibody dramatically reduced its immunogenicity relative to its murine parent molecule, but ADA were present. And in those with neutralizing antibodies, it can be demonstrated that clearance was increased by about 20%. Nonetheless, there was no apparent correlation of antidrug antibodies with the development of the clinical response, adverse reactions or pharmacodynamics. Unfortunately, humanization was not always -- did not always have a successful outcome, as illustrated in the case of bococizumab, which was an anti-PCSK9 antibody developed by Pfizer. And after conducting very large Phase III clinical trials, they halted its development because approximately 50% of subjects developed neutralizing antibodies that completely abrogated the efficacy of the drug. Thus, the impact of humanization on therapeutic antibody immunogenicity is variable. The development of fully human antibodies culminated the efforts of antibody engineers to reduce murine sequences and reduce the adverse events associated with the immunogenicity of monoclonal antibodies. Adalimumab was the first fully human antibody licensed in 2002, but as recorded in this more recent publication, following a single 40-milligram dose, ADA developed to -- in 80% of healthy volunteer subjects in this clinical trial. And all the ADA were neutralizing. And in those who had ADA, there was an 80% reduction in exposure by the end of the study. Thus, even fully human antibodies can be highly immunogenic. And we recognize now that most ADA are anti-idiotypic, which is to say that the ADA shown in red here recognizes the paratope or the CDR3 region of the monoclonal antibody. Why is this the case? Well, most therapeutic antibodies are actually directed against self-antigens. So imagine that you went to your doctor's office, and he drew a blood sample to screen for autoantibodies, and he detected that you had an anti -- circulating anti-PCSK9 antibody or an anti-TNF antibody or an anti-IL17 antibody, he would conclude that you may have an autoimmune disease because of the circulating autoantibodies. Thus, you can view modern therapeutic antibodies as engineered autoantibodies containing CDRs, which are normally deleted during human B-cell ontogeny. This point is illustrated by this data, which is a survey of recently approved monoclonal antibodies. And you can see that here in blue, that among these humanized in human and chimeric antibodies that immunogenicity can vary widely between humanized antibodies, ranging from 5% to 15% and in the chimeric antibodies, they are less immunogenic than fully human antibodies. So -- but what distinguishes these antibodies in blue from these antibodies in red is not just that these are all human, but that these antibodies in red are all directed against foreign antigens, while these antibodies are all directed against self-antigens -- self-proteins. Thus, the takeaway here is that therapeutic monoclonal antibodies that are directed towards self-antigens contain CDR sequences that would have been selected against murine human B-cell ontogeny. Thus, there is a lack of immune tolerance to such CDRs; as a consequence of which, they are recognized as foreign sequences. Therefore, therapeutic monoclonal antibodies are inherently immunogenic vis-à-vis the presence of these CDRs. The ADA that will be elicited to such therapeutic antibodies are anti-idiotypic and thus neutralizing. And given the nature of the immunogenic epitopes, it's unlikely that they can be engineered out without the antibody losing affinity or its specificity. So let me change gears slightly now and talk about ADA not in humans but in nonhuman primates, specifically during preclinical testing. So ADA to human monoclonal antibodies or humanized monoclonal antibodies during preclinical studies can confound the results by reducing the parent PK in the study, such as in this illustration with golimumab in which the loss of exposure temporarily correlates with the development of antidrug antibodies in this PK study. And these ADA can form immune complexes with the therapeutic antibody and precipitate out causing toxicity in the monkey. The immune complexes are shown in these micro photographs of these histological specimens of heart tissue on the left and liver on the right and the arrows pointing to the immune complex deposition. So just as in humans, antidrug antibodies in nonhuman primate studies can cause a number of adverse events that complicates the interpretation of the studies. At JoMoCo, we've developed a means, we've termed it called -- we've termed ADAbate, which we believe will be able to prevent ADA developing in nonhuman privates. And the scientific premise of this is the clinical observation in humans that the ortholog, the human ortholog of ADAbate dramatically inhibits the production of cytokines that are essential for antibody development. Furthermore, in clinical trials, it's been shown that this ortholog prevents the antibody response in subjects vaccinated with the hepatitis A virus and hepatitis B virus vaccines. Interestingly, it's able to selectively inhibit this antibody induction without an increase in susceptibility to infection. Thus, at JoMoCo we hope to apply this to improve preclinical development by preventing antidrug antibodies during such clinical -- during such preclinical studies without inducing broad immunosuppression. We hope to improve the quality of nonhuman primate PK and toxicology studies, accelerate drug development by reducing the number of studies that need to be repeated because they're confounded by antidrug antibodies, reduce the cost of nonhuman primate testing by reducing, one, number of studies that need to be repeated, but also by enabling the reuse of monkeys in PK studies and advance the 3Rs by reducing the overall number of nonhuman primates that are needed to perform preclinical development of human therapeutics. So collectively, we hope that these steps will advance medical research and the development of better biotherapeutics that can reach the clinic more quickly. We are presently conducting collaborative research studies with the Vaccine Research Center and the National Institute of Allergy and Infectious Disease at the National Institutes of Health to test ADAbate in rhesus macaques. And if any of you are interested, we would love to collaborate in such studies in cynomolgus monkeys as well. So thank you very much for joining this session and for your attention. If you have any questions about this talk that I haven't addressed during the chat session or we aren't able to address during the chat session, please feel free to contact me at my e-mail site -- contact me with an e-mail, and thank you again, and enjoy the rest of the meeting.