We spent a week with innovators of antibody therapeutics to learn how we can enhance development from bench to bedside
By Mike Piazza, Associate Director of Applications Development
We recently had the opportunity to attend the Next Generation Antibody Therapeutics meeting in the mountain-backed town of Banff, Calgary, and it was undoubtedly an eye-opening experience for our team. Spending a week with the brightest minds in the industry allowed us to delve deep into the most critical aspects of antibody development, while opening a dialogue for how we, as technology developers, can build better tools to enhance therapeutic potential.
As I bring back a fresh perspective on the industry and prepare to translate our learnings into an actionable roadmap, I wanted to share some of the core themes that I took away from the meeting that will guide the next stage of innovation for our label-free systems.
- It’s the era of multispecifics.
- T-cell costimulation is emerging as an important target.
- Collaboration is key to innovation momentum.
- Binding data is fundamental to predicting clinical potential.
1. It’s the era of multispecifics.
Bispecific and trispecific drugs were the most prevalent drug format discussed at the conference, which is unsurprising given the transformative potential they bring to the pharmaceutical industry.
Bispecific antibodies (BsAbs), which are antibodies created with two binding sites directed at two different antigens or two different epitopes on the same antigen, and trispecifics, which have a third binding site, have proven to be useful as a modality for treatment across a broad range of diseases, including tumor immunotherapy. To date, three BsAbs have received market approval by the FDA, and over 100 others are currently in various stages of clinical trials.1
Current efforts are focused on developing and fine-tuning the multispecific mechanism of action (MoA) to successfully target tumors. For example, some BsAbs connect immune cells to tumor cells, enabling them to exert their killing effect by playing the role of immune cell connector. Others target tumor antigens, blocking dual signaling pathways, while another type targets inflammatory factors in the tumor microenvironment to reduce inflammation and CRS. These versatile MoAs allow for the development of drugs that have enhanced targeting capabilities and greater therapeutic impact compared to conventional drugs, which prevents an attractive opportunity for antibody discovery.
Another interesting aspect of multispecific development is the use of molecular features that were conventionally perceived as counter-intuitive to therapeutic efficacy, such as steric hindrance and lower affinity. For example, dual-variable domain IgGs (DVD-Ig) are generated by combining two target-binding variable domains of two monoclonal Abs to create a dual-specific, tetravalent IgG with treating complex diseases. Some DVD-Igs are being designed with inner and outer binding domains separated by a shorter, cleavable linker to cause steric hindrance of the inner variable domain. This allows for the use of the outer linker to target a cell receptor, which will then get cleaved by proteases to allow the inner domain to respond to a normal antigen.
These are just a few of the many examples presented at the conference on how unconventional methods are being leveraged to engineer better drugs. As more of our SPR users delve into the multispecifics space, we’re excited to build more features to support characterization of these new drug types.
2. T-cell costimulation is emerging as an important target.
T-cell costimulation stood out as a promising target for treating immune-mediated diseases due to its critical role in T-cell activation. Costimulation is used to recruit the immune system to help enhance Signal 1 and Signal 2 in T-cell activation, and is therefore necessary in the induction of the immune response when fighting diseases. Blocking, intervening, or imitating costimulation has been suggested as an effective therapeutic strategy and is being explored by a few key leaders in the field.
Bispecific T-cell engagers (TCEs), for example, are being developed to bind to both a tumor-associated antigen (TAA) with one binding site and to the CD3ϵ chain in the T-cell receptor complex with the other binding site. In a cold tumor, where there is an absence or low T-cell infiltration, using TCEs can restore Signal 1 (CD3 bispecifics) and Signal 2 (CD28 bispecifics) to promote T-cell proliferation and increase overall T-cell count. These TCEs allow for more precision in targeted therapies, and stimulate greater immune responses in the fight against complex diseases.
3. Collaboration is key to innovation momentum.
Meetings such as these highlight how quickly we can advance scientific treatments through open collaboration of academia and industry, and how intelligence sharing is critical to accelerating innovation.
With the COVID-19 pandemic still top of mind for many, the discussion on the Coronavirus Immunotherapy Consortium (CoVIC) was a great case study on how a multi-disciplinary global partnership accelerated the discovery, optimization, and delivery of antibody therapeutics against SARS-CoV-2.
CoVIC is a collaborative effort between experts in academia, industry and government to advance therapeutics to clinic by creating an open forum for pooling antibody resources while allowing contributors to retain their intellectual property. Donated antibodies were subjected to kinetics analysis to determine affinity to target antigens and gain insight into where these mAbs bind to the spike protein. The group also utilized epitope binning to determine neutralizing epitope regions and protection % of mAb therapies, allowing for tracking of protection versus epitope region with each spike mutation over time, and focusing efforts to the epitope groups that would have the most impact in viral neutralization.2
This process of collaboration and mAb pooling created by CoVIC set an excellent framework for therapeutic discovery in future pandemics, and demonstrated the effectiveness of the scientific community working together to advance innovation while contributing to the global knowledge base on viral diseases.
4. Binding data is fundamental to predicting clinical potential.
A key characteristic of a good drug is its ability to bind to its target. Binding data is therefore heavily relied on for determining the potential efficacy and potency of a drug, with the ‘weak binders’ often being eliminated early in the pipeline.
However, circling back to bispecifics, it’s not always efficient to select the ‘best binders’ when determining good bispecific candidates. In some cases, a drug is more potent when one of the binding regions is specific to the tumor-associated antigen but has a lower affinity for the T-cell, as this allows it to find the tumor first and then recruit T-cell after. Higher-affinity T-cell binding can result in higher T-cell binding but lower overall efficacy.
Having reliable data on binding kinetics and the ability to epitope bin antibodies to determine neutralizing epitope regions is necessary for designing effective therapeutics against evolving targets. And one of the biggest needs of scientists today is having access to tools that remove barriers to acquiring this data.
Characterizing therapeutic antibodies with Digital SPR
Alto was a fan favorite at the meeting, as attendees had the opportunity to see the technology live and learn more about its wide range of capabilities. Built for biologics, Alto provides high-throughput analysis of up to 48 unique targets across its 16 channels, while further streamlining user workflows with automated sample dilutions, disposable fluidics, and sample requirements reduced by up to 200X.
In collaboration with Sino Biological, a global leader in recombinant products, we presented on how antibody developers can leverage Alto to accelerate new therapeutic candidates from bench to bedside through crude library screening, binding kinetics characterization, and epitope binning of Sino Biological’s influenza products. Check out the full poster presentation here!
Catch us at our next event to learn more about antibody applications of Digital SPR.
- Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, Huang Y, Xu Y, Qian C. Bispecific Antibodies: From Research to Clinical Application. Frontiers in Immunology. 2021 May 5;12. doi:10.3389/fimmu.2021.626616
- About CoVIC. Coronavirus Immunotherapy Consortium. 2023. https://covic.lji.org/