Introduction Motivations for Next-Generation ADCs 202009

Creative BioLabs is a research organization based in New York that specializes in antibody discovery and engineering. They discuss the motivation behind developing the next generation of antibody drug conjugates (ADCs) for cancer chemotherapy. The first generation of ADCs failed due to suboptimal technologies and limited understanding of the complexities involved. Challenges in using ADCs on patients include predicting their effectiveness and dealing with molecular heterogeneity. However, with continued innovation and collective experience, these challenges can be overcome. Innovations in ADC discovery and development include increasing the number of payloads on each antibody molecule and achieving site-specific conjugation. There is also research on bispecific and bipartotopic ADCs for improved internalization and tumor selectivity. Welcome to Creative BioLabs. 100% of the effort, 100% of the service. As a dynamic contract research organization, we are based in New York and serve the whole world. Our seasoned scientists are skilled in antibody discovery, antibody engineering, and biomanufacturing solutions. Hello everyone. Today we will discuss the motivation of the next generation of ADC development with our scientist, Sony. Hi, Sony, could you explain what's an ADC? The antibody drug conjugate is referred to as ADC. It is a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules, or they are called payloads, through chemical linkers. ADC is a novel therapeutic format and has a great potential in cancer chemotherapy. What is the motivation for developing the next generation ADCs? We need to provide cancer patients with more effective treatment methods so that patients can recover quickly and not suffer as much. Some current drugs have many limitations. For example, immuno-oncology agents. Many patients do not respond at all to immuno-oncology agents, and strategies to personalize treatment for each patient have just began. And certain tumor types, such as acute myelogenous leukemia, have extremely low response rates to immuno-oncology agents. Obviously, a large number of patients need other more effective therapies. Some experts described multiple mechanisms by which ADCs can stimulate anti-tumor immunity. Then, the ADCs stimulate the anti-tumor immune response, and act in synergy with immuno-oncology agents will have better effects. Now, the focus is on the next generation ADCs, so why did the first generation fail? The first generation of ADCs failed because of the suboptimal technologies and a certain ignorance of the complexities of the ADC modality, but the emerging technology and accumulated experience in this field provide new opportunities for next generation ADCs, and make them a more promising therapeutic modality than ever before. What are some challenges you could think of as we begin to use ADCs on patients? Many of the challenges that are more specific to this modality were not appreciated for several decades, but have become strikingly clear with the field's collective experience. First, understanding the anti-tumor activity of ADCs in preclinical models, and predicting their activity in patient populations is a major challenge, even if only because they require rigorous and objective assessment. The preclinical anti-tumor activity must be based on pharmacology, pharmacokinetics, and understanding the effectiveness and limitations of each tumor model, in order to make appropriate predictions of clinical activity. Second, some researchers have observed that, consistent with the ADC treatment hypothesis, the higher the antigen expression, the better the efficacy. But what is easily overlooked, is that the expression level in the preclinical model is compared with that in the patient population. Based on this comparison, the interpretation of the same pharmacological data should be very different. Finally, in addition to some preclinical challenges, the complexity of ADCs has produced a large degree of molecular heterogeneity, in the clinical material of most ADCs, including multiple ADCs approved to be on the market. Although the technical challenges of achieving homogeneous preparations, have long been apparent, the potential advantages of homogeneous preparations are increasingly recognized. Many emerging technologies will increase the complexity of ADCs molecules, which will bring challenges to the manufacturing process. These challenges are not out of reach. In fact, the field of ADCs has reached a turning point. Many technical challenges have been solved through continued innovation, assisted by our collective experience and diligence. We have developed tools and prospects to overcome the challenges, and I'm optimistic that we will succeed. What are the innovations during the discovery and development of ADCs? There are many. I can cite a few typical examples. First, Bodyox Group proposed to deload more payloads on each antibody molecule. Early attempts to increase potency revealed challenges, to maintain adequate pharmacokinetic profiles with negative consequences, for both efficacy and tolerability. These obstacles have been addressed by various approaches, several of which are used in clinical stage ADCs. Second, experts described a multitude of approaches to achieve site-specific conjugation, with the overall goal of producing a homogeneous ADC preparation. That is hypothesized to have increased therapeutic index and other advantages. Then another group proposed the bispecific and bipartotopic antibody drug conjugates, that is, these ADCs can be designed to be more effectively internalized according to molecular form, and thus increase efficacy or exhibit improved tumor selectivity. Some of these concepts have been supported by preclinical research, but the clinical experience of such ADCs is limited.