Shots:
- Unlike hematologic malignancies, where the elimination of most or all tumor cells results in immunosuppression, making headways in solid tumors requires a new holistic approach when using T Cell Engagers
- Abpro’s ABP-102/CT-P72, co-developed by Celltrion leverages a tetravalent format; bivalent for both HER2 and CD3
- PharmaShots welcomes Shaun Murphy, Vice President, Nonclinical Research and Development at Abpro, for a stimulating dialogue exchange highlighting key aspects of T Cell Engagers, like selectivity and safety considerations.
Saurabh: Can you share the scientific rationale behind the design of ABP-102/CT-P72 and its unique tetravalent format? What advantages does this structure offer over other HER2 x CD3 T-cell engagers?
Shaun: The design of ABP-102/CT-P72 was influenced by key lessons learned from earlier T cell engagers, which have been generally limited by safety issues. The tetravalent format of ABP-102/CT-P72, bivalent for both HER2 and CD3, is central to its design advantages. The bivalent HER2-binding domains are designed to exploit avidity effects—favoring activity in the presence of HER2-high expressing tumors while minimizing activity on HER2-low normal tissues, reducing the risk of on-target, off-tumor toxicities that have plagued T cell engagers thus far.
The CD3-binding domains are also designed to enhance safety while retaining anti-tumor activity. While the CD3-binding domains are bivalent, the format of ABP-102/CT-P72 results in the molecule’s activity being similar to one monovalent for CD3, a concept we describe as “functional monovalency.” This functionally monovalent CD3 binding results in lower cytokine production in the presence of HER2-low cells, reducing the risk of cytokine release syndrome (CRS), a major toxicity associated with T cell engagers. The overall format provides a balance between potency and tolerability that we expect to result in a wider therapeutic index than previous HER2 x CD3 T cell engagers.
Saurabh: T-cell engagers targeting solid tumors face several challenges. From your perspective, what lessons has the field learned so far, and how have those informed your approach?
Shaun: The field has learned that applying successful hematologic malignancy strategies directly to solid tumors is not always effective. Unlike hematologic cancers, where elimination of most or all target tumor cells results in acceptable and manageable toxicities such as immunosuppression, more caution must be taken when targeting solid tumors. Often, the therapeutic targets of solid tumors represent proteins expressed on normal tissues, as is true for HER2, which is expressed not only in tumors, but on a wide variety of normal tissues, including the heart and lungs. Thus, our overall design philosophy was to minimize on-target, off-tumor activity to reduce toxicity while maintaining anti-tumor efficacy.
Our approach with ABP-102/CT-P72 reflects this design philosophy. We prioritized features that support tumor-selective activity while avoiding designs that trigger systemic cytokine release leading to CRS.
Saurabh: Selectivity and safety are key considerations for TCEs. How does your molecule aim to balance potent tumor killing with minimizing off-tumor effects and cytokine release?
Shaun: Selectivity was a foundational principle in the design of ABP-102/CT-P72. The molecule leverages avidity for HER2 to ensure that T cell activation is selectively triggered in tumor tissues with high antigen density. Importantly, preclinical data have shown that ABP-102/CT-P72 drives cell killing and cytokine release proportionally to HER2 expression levels—resulting in reduced activity in HER2-low normal cells.
The CD3 arms, engineered for low affinity and functional monovalency, further contribute to safety by limiting unintended T cell activation in the absence of tumor cells. This combination of features has produced a preclinical therapeutic index that suggests the molecule could be both potent and tolerable clinically.
Saurabh: What do you see as the next wave of innovation in bispecific or multispecific antibody therapeutics, especially for solid tumors?
Shaun: Given that tumor selectivity of multispecific antibodies is of paramount importance to reduce on-target, off-tumor toxicities, innovations to achieve this goal are likely to be well-represented in the next wave of multispecific therapeutics targeting solid tumors. Also, given that the safety and efficacy of anti-tumor multispecific antibodies depends on disease and tumor-specific differences in factors such as target biology and tumor heterogeneity, and each innovation comes with its own limitations, it is likely that no one innovation will be a one size fits all solution.
In addition to our avidity-based selectivity approach, other areas of innovation are emerging. One is the use of prodrug multispecific antibodies that are prevented from binding their targets through the use of a molecular mask, which is then cleaved in the tumor by tumor-associated proteases, revealing the active drug. However, as there are no truly tumor-specific proteases, and that tumor-associated proteases are also associated with many other physiological or inflammatory processes, these masked drugs could become active in sites other than the tumor, leading to toxicities.
Conversely, given the heterogeneity of tumors, not all tumors express the requisite proteases for unmasking, potentially leading to inefficient mask cleavage in the tumor and reduced anti-tumor efficacy. Unlike masked prodrug therapeutics being developed, the selectivity of ABP-102/CT-P72 is inherent in the molecule and requires no endogenous proteases or other physiological processes to become an active drug, thus avoiding these potential pitfalls
Another innovation is increasing tumor selectivity by requiring the targeting of multiple tumor antigens simultaneously to exert the anti-tumor effect. While this can lead to a highly tumor-selective therapeutic, there exist significant engineering challenges to produce this dual-binding requirement for therapeutic activity. In addition, tumor target heterogeneity could severely restrict the number of patients in which this class of therapeutics would be useful.
We’re also seeing interest in non-CD3 approaches for engaging T cells or modulating the immune system, as well as new delivery mechanisms like nucleic acid-based platforms.
Saurabh: Abpro is collaborating with Celltrion on ABP-102/CT-P72. How do partnerships like this help advance novel biologics in complex therapeutic areas?
Shaun: In today’s environment, partnerships are essential for bringing complex biologics like T cell engagers to the clinic. Drug development is a long, resource-intensive process, and collaboration allows companies to pool complementary expertise—whether that’s in manufacturing, clinical development, or regulatory strategy.
Our partnership with Celltrion brings together Abpro’s platform and scientific insight with Celltrion’s biologics manufacturing and commercialization capabilities. This kind of collaboration can accelerate the development of next-generation therapeutics and ultimately help deliver them to patients faster.
About the Author:
Shaun Murphy
Shaun Murphy, Ph.D., is Vice President of Nonclinical Research and Development at Abpro, where he leads pharmacology and toxicology across in vitro, preclinical, and clinical studies. Since joining Abpro in 2014, he has held roles of increasing responsibility and played a key role in advancing immuno-oncology programs toward the clinic. Previously, he served as Study Director at Toxikon Corporation (acquired by LabCorp). Shaun earned his Ph.D. in Pathobiology from Brown University and a B.S. in Biology from UMass Boston.
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