Traditional chemotherapy is cytotoxic, whereas targeted therapies specifically attack cancer cells while sparing normal cells. This approach offers high efficacy with low toxicity. Targeted drugs are generally categorized into two types: small molecules and large molecules, which include mAbs, peptides, and ADCs. These targeted drugs can also be used in combination with chemotherapy.

Most targeted therapies work by interfering with specific proteins that assist in tumor growth and spread^[1][2]. For example:

1. Targeting immune checkpoints like PD-1/PD-L1 to help the immune system destroy cancer cells;
2. Disrupting signaling proteins like EGFR, HER2, and mTOR to prevent cancer cell growth;
3. Inhibiting angiogenesis signals like VEGF/VEGFR, to block the supply of oxygen and nutrients to cancerous cells.

Small Molecule Drugs

Small molecule targeted compounds focus on molecules associated with tumor development. They typically regulate the activity of protein targets. Over the past few decades, research on molecularly targeted cancer drugs has led to the successful clinical introduction of many small molecule therapies. Most of these therapies inhibit key cancer targets, including EGFR, VEGFR, ALK, mTOR, matrix metalloproteinases (MMPs), heat shock proteins (HSPs), and proteasomes^[3][4][5].

Antibody Drugs

Therapeutic antibodies exert their effects through various mechanisms:

1. Directly inhibiting tumor cell proliferation by inducing apoptosis or blocking key growth pathways;
2. Mediating antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) to kill tumor cells;
3. Recruiting and activating immune cells like T cells, to recognize and attack cancer cells.
4. Delivering cytotoxins, such as immunotoxins or ADCs, to kill tumor cells.

Monoclonal antibodies are hailed as prototypical ‘magic bullets’ due to their inherent specificity against invading pathogens, with fewer adverse effects. Popular antibody targets include BCMA, CD19, CD20, EGFR, HER2, VEGF-R, Claudin-18.2, CTLA-4, PD-1/PD-L1, and TIGIT^[6][7].

ADCs, often referred to as 'magic biological missiles,' are anticipated to herald a new era in targeted anti-cancer therapies. At the 2023 ASCO and ESMO meetings, ADC drugs dominated the spotlight, with a focus on targets like EGFR, B7-H3, TROP2, CLDN18.2, and c-MET.

HER2

HER2 is a member of the epidermal growth factor receptor (EGFR) family, which also includes EGFR, HER3, and HER4. It can dimerize with other family members. Upon ligand binding, HER2 becomes activated and initiates signaling pathways that regulate cell proliferation and differentiation. HER2 is overexpressed in various cancers, including breast, gastric, lung, and ovarian cancers. Over the past two decades, numerous HER2-targeted therapies for breast cancer have been developed. Many of these therapies are now approved or in clinical trials. HER2 plays a crucial role in research involving small molecules, mAbs, ADCs. T-DM1 and Trastuzumab Deruxtecan are FDA-approved HER2-targeting ADCs used in the treatment of HER2-positive breast cancer^{[8][9][10][11]}.

EGFR

Epidermal growth factor receptor (EGFR) gene mutations and overexpression are common in many human cancers, including lung cancers. These mutations and overexpressions are key targets in cancer therapy.

Various first, second, and third-generation EGFR tyrosine kinase inhibitors (TKIs) have demonstrated effectiveness as anti-cancer therapeutics. There are currently over 20 fourth-generation TKIs in clinical trials, such as EAI045, JBJ-04-125-02, and BLU-945. Additionally, at ASCO, the clinical phase I study data for the world's first EGFR/HER-3 dual-targeting ADC showed promising results. This ADC has the potential to overcome resistance, enhance synergy, and provide strong anti-cancer effects. The accumulated experience and promising outlook have led to EGFR being hailed as a "golden target."

Claudin-18.2

Claudin-18.2 (CLDN18.2) is a member of the tight junction protein families. It is linked to the proliferative and invasive properties of tumors. CLDN18.2 is abnormally expressed in various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). Several CLDN18.2-targeted strategies have been developed, including mAbs, BsAbs, chimeric antigen receptor T (CAR-T) cells, and ADCs. These strategies show promising results. The successful Phase III trial of Zolbetuximab has highlighted CLDN18.2 as a rising star in gastric cancer therapy^[12][13].

TROP2

TROP2 is a transmembrane glycoprotein that is highly expressed in many cancers. It plays a crucial role in tumor cell proliferation, apoptosis, and invasion. This involvement impacts both the treatment and prognosis of cancer patients. As a prognostic marker, TROP2 holds significant promise as a broad-spectrum anti-tumor target. The 2023 ESMO conference shows, two TROP2-targeted ADCs, SKB264 and DS-1062 (Dato-DXd), demonstrated remarkable clinical performance in the treatment of NSCLC and TNBC^[15].

Multi-functional GLP-1RA peptides demonstrate superior efficacy, but their administration is still limited now. Some researchers have moved their eyes to small-molecule GLP-1RA - with high oral bioavailability, and high patient compliance. This new avenue has yet to see a standout success, with Orforglipron emerging as a leading contender, showing promising results in blood sugar control and weight management according to clinical trials^[14][15]. The development of small molecule GLP-1RAs provides a new option for obese and T2D individuals who have been undergoing long-term injection therapy.

B7-H3

B7-H3 (CD276) is an immune checkpoint molecule and a dual-function immunoregulatory protein. It plays both costimulatory and coinhibitory roles in the immune system. B7-H3 is overexpressed in a variety of cancers. Its elevated levels have been linked to increased cell proliferation and enhanced invasiveness in several cancer types, including pancreatic, breast, colorectal, and prostate cancer. The latest follow-up data from Ifinatamab deruxtecan (I-DXd) trials offer new hope for SCLC treatment. While no B7-H3 ADCs have been approved yet, over 40 are in clinical stages globally. This makes B7-H3 a promising target for future therapies^[16].

About MCE

MCE offers over 10,000 catalog recombinant proteins covering drug target proteins, including receptor proteins, enzymes, immune checkpoint proteins, CAR-T-related proteins, and more. MCE also supports custom services for recombinant proteins, ADCs, PROTACs, and one-stop drug screening services.