The oncology target landscape has long been dominated by a handful of well‑characterised molecules—HER2, PD‑1, CD19—each with their own blockbuster drugs and established clinical pathways. But the most exciting developments in precision oncology are increasingly coming from targets that sit slightly off‑centre: receptors that were once considered "undruggable," co‑stimulatory molecules that were overlooked, and signalling nodes that only revealed their true importance when resistance to existing therapies emerged.
Among these emerging and re‑emerging targets, HER3 , EGFR , and CD2 represent three distinct pillars of modern oncology research. HER3 is the long‑overlooked member of the EGFR family now driving a new wave of antibody‑drug conjugate development. EGFR is the established classic that continues to yield surprises—and resistance mechanisms—more than two decades after its discovery. And CD2 is the immune co‑stimulatory receptor that is finally getting its moment, redefining how we think about T cell engagement and CAR‑T cell engineering. Together, they illustrate the full spectrum of target discovery: from resurrection, to refinement, to reinvention.
HER3: From the "Orphan" Receptor to ADC Darling
For years, HER3 was the neglected member of the EGFR family. Unlike HER2, it lacked intrinsic kinase activity; unlike EGFR , it had no obvious activating mutations to target. It was dismissed as a "pseudo‑kinase"—a receptor that couldn't signal on its own and therefore wasn't worth pursuing. That narrative has changed dramatically.
HER3 is now recognised as a significant pro‑cancer factor across multiple tumour types due to its overexpression and abnormal activation, which initiates downstream signalling pathways crucial for cancer cell survival and progression. Its ability to form heterodimers with other ErbB receptors enables it to activate pathways that promote tumour growth and survival—particularly in cancers that have acquired resistance to other targeted therapies. Increased cell surface density of HER3 is observed on tumour cells that acquire resistance to a growing number of clinical targeted therapies, making it a marker of therapeutic escape.
The clinical validation of HER3 as a therapeutic target has come through the development of HER3‑directed antibody‑drug conjugates (ADCs).
Beyond traditional ADC formats, HER3 has also enabled entirely new delivery paradigms. Researchers have developed systemic HER3 ligand‑mimicking nanobioparticles that can cross the blood‑brain barrier and reduce intracranial tumour growth, offering a targeted approach for metastatic tumours localising to the brain. These developments have positioned HER3 as one of the most dynamic oncology targets in current research.
EGFR: The Classic Target That Keeps Revealing New Layers
If HER3 is the rising star, EGFR is the established classic—but it is far from a closed chapter. The discovery of activating mutations in the EGFR gene revolutionised the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). Yet the story of EGFR is also a story of resistance, and it is this very resistance that continues to drive innovation.
In EGFR‑mutant non‑small cell lung cancer, third‑generation TKIs like osimertinib have become standard of care, but resistance inevitably emerges. Recent clinical data have shown that combination approaches—such as amivantamab plus lazertinib—can significantly extend overall survival compared to osimertinib alone in treatment‑naïve patients with EGFR mutations. Meanwhile, newer agents are being evaluated in the post‑TKI resistance setting.
The challenge of resistance is perhaps even more pronounced with anti‑EGFR antibody therapies. Cetuximab and panitumumab are widely used for colorectal cancer, but various mechanisms of resistance limit patient responses. Recent research has identified EGFR S442 ectodomain mutations as drivers of cetuximab resistance, highlighting co‑targeting ERBB2 as a therapeutic strategy to restore anti‑EGFR efficacy. Novel antagonistic EGFR antibodies that bind epitopes overlapping but distinct from the cetuximab‑binding site have been developed to overcome acquired resistance. Multiparatopic antibodies that induce targeted degradation of EGFR mutants—independent of the driver mutations typically residing in the cytosolic domain—represent a mechanistically distinct strategy to overcome TKI resistance by directly degrading the target oncoprotein.
These advances underscore that EGFR remains a fertile ground for therapeutic innovation—not despite resistance, but because of it.
CD2: The Co‑stimulatory Receptor Finally Getting Its Moment
While HER3 and EGFR operate in the realm of tumour cell signalling, CD2 belongs to a different world entirely: the immune synapse. CD2 is a key costimulatory receptor on human T cells, serving important functions in cell adhesion and recognition. Its relevance to cancer immunotherapy has become increasingly clear as researchers have recognised that T cell engagers (TCEs)—despite clinical success in haematologic malignancies—have had limited therapeutic success in solid tumours, partly due to insufficient costimulatory signals in the tumour microenvironment.
Recent single‑cell RNA sequencing data from multiple solid tumour types has revealed that tumour‑infiltrating T cells express high levels of CD2 but not CD28 or other costimulatory receptors, making CD2 an attractive and uniquely positioned target for costimulation. The EVOLVE platform—a trispecific T cell engager with integrated CD2 costimulation—has shown that CD2 costimulation is superior in maintaining T cell viability and effector function relative to other pathways. This integrated platform represents a next‑generation TCE approach that increases T cell effector function in the tumour microenvironment.
The potential of CD2 extends far beyond TCEs. A novel CD2 ‑targeted costimulatory bispecific antibody platform (BiTco) provides costimulation to T cells via CD2 in the context of a tumour‑associated antigen. Notably, CD2 BiTco molecules trigger markedly less cytokine release compared to CD28 bispecifics—making them a potentially safer clinical option—while still providing robust costimulation to CD28‑negative CD8 T cells, a population that constitutes the majority of CD8 T cells found in elderly patients.
Collectively, these findings position CD2 as a target with dual relevance: both as a direct target for CAR‑T cell therapy and as a critical costimulatory protein whose signalling can be rescued to improve therapeutic outcomes.
How to Choose and Buy?
At BOT Bioscience , we are committed to providing premium-quality Oncology Targets to support your cutting-edge research in precision oncology, immunotherapy, and drug discovery. Our oncology target portfolio features:
High purity and biological activity validated across multiple applications
Broad coverage of tumour-associated antigens, immune checkpoints, and co-stimulatory receptors
Multiple formats: recombinant proteins with various fusion tags (Fc, His, Avi, etc.) and antibodies in diverse clones and conjugations
Multiple labelling options: biotin, APC, PE, FITC, and other fluorophores for multicolour flow cytometry and imaging
Rigorous quality control for consistent batch-to-batch performance
Custom protein expression, antibody development, and conjugation services upon request
For researchers interested in exploring Oncology Targets for ADC development, immunotherapy research, or resistance mechanism studies, BOT Bioscience offers comprehensive technical support and customisation services to meet your specific project requirements. Please Contact us or send an email at info@bot-bioscience.com for product inquiries, quotations, and more detailed information.