Members of the human epidermal growth factor receptor (HER) family, including HER1 (EGFR), HER2, HER3, and HER4, play central roles in regulating cell proliferation, survival, differentiation, and migration. Overexpression of the EGFR family is considered to be one of the most common cellular disorders associated with various tumor types.
Antibody drug conjugates (ADCs) are a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with the cytotoxicity of chemotherapeutics. The FDA approved two HER2-directed ADCs, trastuzumab emtansine, and trastuzumab deruxtecan, in 2013 and 2019, respectively, for the treatment of HER2-positive metastatic breast cancer.
In 2021, the NMPA approved a third HER2-directed ADC, disitamab vedotin, for locally advanced or metastatic gastric or gastroesophageal junction cancer. Currently, a total of 11 ADCs targeting HER family receptors (EGFR, HER2 or HER3) are undergoing clinical trials. The success of these drugs has transformed the treatment of HER-positive cancers and breathed new life into the field of ADC development.
Targeted drugs targeting HER
Due to the critical role of the HER family in carcinogenesis, two major targeted therapies have been developed over the past two decades to block HER-driven pathways, which include small molecule compounds that inhibit the activity of intracellular domain tyrosine kinases, and a monoclonal antibody directed against the extracellular domain (ECD) of the receptor.
- Tyrosine kinase inhibitors (TKIs)
Eight tyrosine kinase inhibitors (TKIs) have been approved for clinical use, and they tightly bind to the kinase domain of the HER family.
The first-generation TKIs of the HER family include erlotinib, gefitinib, and lapatinib. Erlotinib and gefitinib selectively bind to the ATP-binding site of EGFR and are the only two single-target TKIs so far, while lapatinib is the first TKI approved for breast cancer, Shows equal activity against EGFR and HER2.
Next-generation TKIs including afatinib, dacomitinib and neratinib are irreversible pan-HER2 inhibitors (EGFR, HER2 and HER4), afatinib and dacomitinib are approved for non-small cell Lung cancer (NSCLC), while neratinib is approved for breast cancer. Among the six TKIs mentioned above, erlotinib, gefitinib and afatinib are still the first-line treatment drugs for non-small cell lung cancer.
Finally, osimertinib is a third-generation EGFR TKI with significant efficacy in NSCLC patients with EGFR activating mutations and EGFR T790M mutations.
- Monoclonal antibody
Unlike TKIs, monoclonal antibodies bind to the extracellular domain of the receptor, thereby preventing the receptor from binding to the ligand or its dimerization. So far, several monoclonal antibodies targeting HER receptors have been approved for clinical use.
There are currently two HER2-targeting mAbs on the market, including trastuzumab and pertuzumab. Trastuzumab has been widely used in the treatment of HER2-positive breast cancer and gastric cancer, while pertuzumab has been used in the treatment of HER2-positive breast cancer.
To date, five EGFR-targeting monoclonal antibodies have been approved for clinical use, namely cetuximab, panitumumab, nimotuzumab, necitumumab, and amivantamab. Cetuximab and panitumumab are both approved for metastatic colorectal cancer (CRC), and cetuximab is also approved for KARS wild-type CRC and advanced squamous cell carcinoma. Nimotuzumab is approved for the treatment of squamous cell carcinoma of the head and neck, and necitumumab is approved for the treatment of refractory metastatic squamous non-small cell lung cancer. Unlike the anti-EGFR monoclonal antibodies mentioned above, amivantamab is a bispecific antibody that can simultaneously bind the extracellular domains of EGFR and MET.
ADC targeting EGFR
EGFR is amplified or overexpressed in various tumor types and has been proven to be an important tumor target. Currently, there are three EGFR-targeting ADCs in clinical research, including depatuxizumab mafodotin (ABT-414), MRG003, and M1231.
- Depatuxizumab-Mafodotin（ABT-414）
ABT-414 consists of an EGFR-specific humanized antibody (ABT-806), a non-cleavable maleimide hexyl (mc) linker, and monomethylgenastatin F (MMAF), with an average amount of MMAF bound to each monoclonal antibody of approx. for 4.
- MRG003
MRG003 consists of a fully human EGFR-specific IgG1 antibody, a protease-cleavable valine citrulline (vc) linker and monomethyl auristatin E (MMAE). MRG003 showed acceptable safety and potential antitumor activity.
- M1231
M1231 is an exploratory ADC in which a stauromycin-related payload is combined with a bispecific antibody targeting both MUC1 and EGFR. Stauromycin is a tripeptide that exerts its cytotoxicity by binding to tubulin, thereby disrupting normal microtubule dynamics.
ADC targeting HER2
HER2 is another important target for the treatment of HER family cancers.
- Trastuzumab duocarmazine
Trastuzumab duocarmazine is a HER2-targeted ADC consisting of the main body of trastuzumab conjugated to a cleavable linker and a ducamycin payload. The payload is membrane permeable and thus has the potential to enter neighboring cells regardless of HER2 expression.
- A166
A166 consists of trastuzumab conjugated to duostatin-5, an auristatin derivative.
- XMT-1522
XMT-1522 is an ADC composed of the backbone of the HT-19 antibody. HT-19 is a human IgG1 anti-HER2 monoclonal antibody that binds to domain IV of HER2 to form an epitope distinct from the binding site of trastuzumab, with a payload of auristatin derivative (AF-HPA).
- ALT-P7（HM2/MMAE）
ALT-P7 is a novel HER2-targeting ADC consisting of a variant of trastuzumab conjugated to MMAE.
- ARX788
ARX788 is a site-specific ADC consisting of an anti-HER2 antibody conjugated to AS269, a highly potent tubulin inhibitor, using a unique unnatural amino acid conjugation technique and a non-cleavable linker.
- PF-06804103
PF-06804103 is a trastuzumab-derived antibody conjugated to AUR-06380101, a novel and potent auristatin derivative, via a cleavable linker. PF-06804103 showed efficacy in breast, gastric and lung tumor models with low HER2 expression.
- MRG002 and ZW49
MRG002 and ZW49 are two ADCs. They all use auristatin as payload conjugated to different HER2 mAbs. The former uses a humanized anti-HER2 IgG1 monoclonal antibody. The latter uses ZW25, an anti-HER2 bispecific antibody that recognizes the binding sites of trastuzumab and pertuzumab, respectively.
- BDC-1001
BDC-1001 consists of a biosimilar of trastuzumab conjugated to a TLR 7/8 agonist via a non-cleavable linker. BDC-1001 is able to activate antigen-presenting cells while preserving antibody-mediated effector functions, such as ADCC. Preclinical data showed that BDC-1001 induced potent immune-mediated anti-tumor effects in xenograft models and demonstrated its safety in a human study for the first time.
ADC targeting HER3
HER3 is overexpressed in several cancer types and is thought to predict poor prognosis. Despite lacking significant kinase activity, HER3 exerts its function through HER3 homodimerization or HER2/HER3 heterodimerization, thereby activating downstream signaling pathways to promote cell survival and proliferation. Importantly, HER3 signaling has been shown to be involved in resistance mechanisms to anti-EGFR/HER2 therapies and is emerging as a promising therapeutic target in EGFR-mutant NSCLC.
- Patritumab deruxtecan (U3-1402)
Patritumab deruxtecan (U3-1402) is currently the only ADC in clinical research. U3-1402 consists of an anti-HER3 monoclonal antibody (Patritumab), a cleavable GGFG linker, and the topoisomerase I inhibitor Dxd. Studies have shown that U3-1402 has good anti-tumor activity and has a tolerable safety profile.
Challenges and prospects of ADC development
- Challenges
1) How to improve the uptake of ADCs by cancer cells has always been a major challenge in the development of ADCs. Currently, ADCs rely on high levels of target antigen expression on the cancer cell surface to ensure efficient endocytosis to release cytotoxic payloads. The level of expression of target antigens on the tumor surface significantly limits the therapeutic efficacy of existing ADCs.
2) Systemic toxicity is still one of the main factors leading to the failure of ADC clinical trials. Toxic effects are related to multiple factors, including antibody, payload drug, linker, and target antigen.
3) New resistance to ADC therapy is another hurdle to overcome.
- Development
1) Recombinant antibody approaches could be explored to improve cancer cell delivery and lysosomal trafficking of ADCs.
2) In next-generation ADCs, it is necessary to develop novel payload platforms, linker technologies, and conjugation strategies to maximize therapeutic efficacy and minimize ADC toxicity.
3) Clinical and translational approaches will also play a key role in improving the therapeutic window of ADCs. Combination therapy is believed to have the ability to improve drug efficacy and reduce ADC resistance. In addition, optimizing patient selection and monitoring clinical biomarkers for response signals could also improve the therapeutic index of ADCs.