March 5, 2024

Medical Trend

Medical News and Medical Resources

How does ADC target HER family in tumor therapy?

How does ADC target HER family in tumor therapy?



 

How does ADC target HER family in tumor therapy?

Members of the human epidermal growth factor receptor ( HER ) family, including HER1 ( EGFR ), HER2, HER3 and HER4, play a central role 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 US Food and Drug Administration ( FDA ) approved two HER2-directed ADCs, trastuzumab-emtansine ( T-DM1 ) and trastuzumab-deruxtecan ( DS-8201a ), in 2013 and 2019, respectively, for the treatment of HER2-positive metastases sexual breast cancer.

 

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 against the extracellular domain ( ECD ) of the receptor.

 

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.

 

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 ( Herceptin® ) and pertuzumab ( Perjeta® ). 

Trastuzumab, first approved in 1998, has been widely used to treat HER2-positive breast and gastric cancer, while pertuzumab was approved in 2012 and has been used to treat HER2-positive breast cancer since 2012.

 

Dual blockade of HER2 with trastuzumab and pertuzumab has become a first-line treatment for patients with metastatic breast cancer.

 To date, five EGFR-targeting monoclonal antibodies have been approved for clinical use, namely cetuximab ( Erbitux® ), panitumumab ( Vectibix® ), nimotuzumab ( BIOMAB-EGFR® ), necitumumab ( Portrazza® ) and amivantamab ( Rybrevant® ). 

Cetuximab and panitumumab are both approved for metastatic colorectal cancer ( CRC ), and cetuximab is also approved for the treatment of 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 mAbs mentioned above, amivantamab is a bispecific antibody that binds to the extracellular domains of both EGFR and MET and has recently been approved for the treatment of advanced or metastatic NSCLC with EGFR exon 20 insertion mutations adult patients.

 


ADC targeting EGFR

EGFR is amplified or overexpressed in various tumor types and has been proven to be an important tumor target. However, there are currently no ADCs targeting EGFR approved for cancer treatment. Currently, there are three EGFR-targeted ADCs in clinical studies, including depatuxizumab mafodotin ( ABT-414 ), MRG003, and M1231. ABT-414 is by far the most advanced EGFR-targeted ADC and has entered Phase III clinical trials.

 

How does ADC target HER family in tumor therapy?

 

Depatuxizumab-Mafodotin(ABT-414)

ABT-414 consists of an EGFR-specific humanized antibody ( ABT-806 ), a non-cleavable maleimide hexyl ( mc ) linker and monomethylaurinastatin F ( MMAF ), with each The average number of MMAF bound by each monoclonal antibody is about 4. 

ABT-806 binds to a cryptic epitope in the cysteine-rich domain ( CR1 ) of EGFR. Compared with other EGFR-targeting antibodies, ABT-806 has the lowest binding activity to EGFR in normal tissues. ABT-806 414 retains the excellent binding and functional properties of ABT-806.

 

In a phase I clinical trial ( NCT01800695 ), the safety, pharmacokinetics and antitumor efficacy of ABT-414 as monotherapy or in combination with temozolomide in patients with glioblastoma were explored. ABT-414 demonstrated a manageable safety profile and an acceptable pharmacokinetic profile in a phase I trial.

However, the primary endpoint of overall survival was not met in the Phase 2 clinical study ( NCT02343406 ). A Phase II/III study ( NCT02573324 ) is currently ongoing in participants with newly diagnosed glioblastoma with EGFR amplification. However, the trial was terminated in 2019 due to lack of survival benefit.

 

MRG003

MRG003 consists of a fully human EGFR-specific IgG1 antibody, a protease-cleavable valine citrulline ( vc ) linker and monomethyl auristatin E ( MMAE ). 

MRG003 has undergone Phase I clinical trials ( CTR20180310, NCT04868344 ) to evaluate the safety, pharmacokinetics and efficacy of MRG003 as a single agent in patients with relapsed or refractory solid tumors. Encouragingly, MRG003 showed acceptable safety and potential antitumor activity. 

Multiple Phase II studies of MRG003 ( NCT05126719, NCT04868162, NCT04838964, and NCT04838548 ) are currently ongoing in patients with recurrent or metastatic nasopharyngeal carcinoma, head and neck squamous cell carcinoma, advanced metastatic biliary tract carcinoma, and advanced non-small cell lung cancer middle.

 

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. 

Detailed structural information and preclinical data of M1231 have not yet been published. A Phase I clinical study ( NCT04695847 ) is currently underway as a monotherapy in patients with metastatic solid tumors, esophageal cancer, and NSCLC.

 

ADC targeting HER2

HER2 is another important target for the treatment of HER family cancers. 

So far, there are three HER2-targeted ADCs on the market, and T-DM1 ( Kadcyla ) is the first Her2-targeted ADC drug approved by the FDA for the treatment of advanced HER2+ breast cancer, and is also approved for neoadjuvant therapy Early high-risk patients with residual disease. 

In 2019, T-DXd ( DS-8201; ENHERTU ) became the second approved novel Her2-targeted ADC drug, which showed significant anti-tumor activity in the treatment of patients with refractory Her2+ metastatic breast cancer. 

In addition, in 2021, Rongchang Biotech’s RC48 was approved for marketing in China for the treatment of patients with locally advanced or metastatic gastric cancer with Her2 overexpression who have received at least 2 types of systemic chemotherapy.

 

How does ADC target HER family in tumor therapy?

 

Currently, a number of next-generation HER2-targeting ADCs are currently being investigated in clinical trials. These novel drugs are designed with different payloads and attachment techniques to further enhance their efficacy and tolerability. These studies illustrate future directions for the treatment of patients with HER2-positive solid tumors.

How does ADC target HER family in tumor therapy?

 

Trastuzumab duocarmazine

Trastuzumab duocarmazine ( SYD985 ) is a HER2-targeting 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. 

A Phase 1 study of this ADC showed acceptable toxicity and antitumor activity in HER2-positive and HER2-low breast cancer.

n this extension study of patients with HER2-positive MBC, 33% of patients ( 16/48 ) achieved an objective response.

 

These results formed the basis of the phase III TULIP trial ( NCT03262935 ), enrolling T-DM1-treated patients with HER2-positive MBC and assessing PFS as the primary endpoint, the results of which have not yet been reported. SYD985 is also currently being studied in combination with paclitaxel ( NCT04602117 ) and niraparib ( NCT04235101 ). 

SYD985 in combination with doxorubicin and cyclophosphamide is also being investigated in the I-SPY trial ( NCT01042379 ), a large adaptive neoadjuvant trial evaluating pathological complete response ( pCR) to different biologics in combination with chemotherapy )Rate.

 

A166

A166 consists of trastuzumab conjugated to duostatin-5 ( an auristatin derivative ). In 2020, results from a Phase I trial ( NCT03602079 ) in 27 evaluable patients showed a DCR of 59%, with PR observed in 7 patients ( 26% ) at dose levels of 3.6 mg/kg and 4.8 mg/kg . The study is ongoing.

 

IOM-1522

XMT-1522 is an ADC composed of the antibody backbone of HT-19, a human IgG1 anti-HER2 monoclonal antibody that binds to domain IV of HER2 to form a different form of trastuzumab binding site bit, the payload is an auristatin derivative ( AF-HPA ). 

Preclinical data show that XMT-1522 is effective against HER2-positive BC and gastric cancer cell lines as well as T-DM1-resistant xenograft models.

 Preliminary results from a Phase I study ( NCT02952729 ) showed an overall DCR of 83% ( 5/6 in the doses of 16 and 21.3 mg/m2, with 1 PR, at doses below 16 mg/m2 Among patients, DCR was 25% ( 3/12 ).

 

ALT-P7(HM2/MMAE)

ALT-P7 is a novel HER2-targeting ADC consisting of a variant of trastuzumab conjugated to MMAE. 

Results from the first-in-human study showed a DCR of 77.3% ( 17/22 ) of measurable patients with 2 PRs. In patients with a median of 6 prior treatments, the median PFS was 6.2 months, and a phase 2 study is currently planned.

 

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. The results of the phase 1 trial showed anti-tumor activity in HER2-positive BC.

Among 48 evaluable patients, the ORR was 56% in the 1.3mg/kg dose group, and the ORR increased to 63% at the 1.5mg/kg dose. 

As a result, the FDA granted Fast Track designation in January 2021. 

ARX788 is currently being evaluated in a two-part Phase 1 dose-escalation trial ( NCT03255070 ) in patients with HER2-positive solid tumors.

 

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. 

Preliminary results from a dose-escalation Phase 1 study ( NCT03284723 ) showed an ORR of 52.4% ( 11/21 ) at doses ≥3.mg/kg. All patients had previously received HER2-targeted therapy, with a median of 6 prior treatments.

 

MRG002 and ZW49

MRG002 and ZW49 are two ADCs that both use auristatin as the payload coupled to different HER2 monoclonal antibodies, the former uses a humanized anti-HER2 IgG1 monoclonal antibody, and the latter uses ZW25, a drug that recognizes trastuzumab and pertuzumab binding respectively Anti-HER2 bispecific antibody.

Two ADCs are currently in Phase 1 clinical trials ( CTR20181778, NCT04492488, NCT04742153, NCT03821233 ).

 

BDC-1001

BDC-1001 consists of a biosimilar of trastuzumab 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.

 Efficacy results for BDC-1001 alone or in combination with anti-PD1 are still pending ( NCT04278144 ).

Finally, a novel design of pertuzumab-based ADCs with reduced affinity for HER2 at acidic endosomal pH, such a design showing increased lysosomal delivery and cytotoxicity in a HER2 low-expression xenograft model, is expected to move into further studies. Clinical Trials.

 

 


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 ) is the only ADC currently in clinical studies.

 

U3-1402 consists of an anti-HER3 monoclonal antibody ( Patritumab ), a cleavable GGFG linker, and the topoisomerase I inhibitor Dxd. 

With a DAR of 8, U3-1402 exhibits high HER3-specific binding affinity in other human HER family receptors, including EGFR, HER2, and HER4 , and has also been shown in patient-derived xenograft models Potent antitumor activity with acceptable safety profile. 

Currently, a Phase I/II study ( NCT02980341 ) of U3-1402 in HER3-positive metastatic breast cancer is ongoing. Early reports from this trial indicated that U3-1402 had promising antitumor activity with a tolerable safety profile. 

Meanwhile, U3-1402 is conducting a phase I clinical study ( NCT03260491 ) to explore the efficacy and safety in metastatic or unresectable non-small cell lung cancer.

 

 

 


Challenges and Prospects of ADC Development

As one of the fastest-growing anticancer drugs, ADCs currently face three major 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. Studies have shown that efficient cell killing by HER2-targeting ADCs is often correlated with the level of HER2 expression on the cell surface and generally requires a rather high level of surface HER2 expression. The level of expression of target antigens on the tumor surface significantly limits the therapeutic efficacy of existing ADCs. Therefore, increasing the uptake of ADCs to cancer cells has the potential to meet more market demands, especially for patients with low levels of antigen expression.

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. Studies have shown that ineffective internalization and lysosomal trafficking or degradation of ADCs may be the main mechanism of T-DM1 resistance. In addition, antibody-related resistance mechanisms may also contribute to T-DM1 resistance, including reduced expression of HER2, expression of truncated forms of HER2, or mutations in the ERBB2 gene.

 

To overcome the above challenges, future development directions of ADCs may include:

1) Recombinant antibody approaches could be explored to improve cancer cell delivery and lysosomal trafficking of ADCs. Such as bispecific antibodies and antibodies conjugated to cell-penetrating peptides to improve cancer targeting and lysosomal delivery of ADCs.

2) There is still a great need for improvements in ADC design. In next-generation ADCs, it is necessary to develop new 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.

 

 

 


Summary

HER-targeted ADCs are becoming a very promising treatment for patients with HER-positive cancers, three anti-HER2 ADCs ( T-DM1, DS-8201a, and RC48 ) are approved for HER2-positive cancers, and 11 HER-targeted ADCs are currently in clinical trials middle.

 

The innovative molecular structure, combined with antigen specificity and potent cytotoxicity, endows ADC therapy with unique pharmacodynamic and pharmacokinetic properties. 

The efficacy of next-generation ADCs against HER2 poorly differentiated tumors has the potential to change the historical paradigm of HER-targeted therapy. 

With the success of T-DM1, T-DXd and RC48, a large number of novel HER-targeting ADCs with good activity are currently being studied, and these drugs will bring new hope for the treatment of HER+ cancers.

 

 

 

 

 

references:

1.Antibody-Drug Conjugates Targeting theHuman Epidermal Growth Factor Receptor Family in Cancers. Front Mol Biosci. 2022;9: 847835.

2. Implementing antibody-drugconjugates (ADCs) in HER2-positive breast cancer: state of the art and futuredirections. Breast Cancer Res. 2021; 23: 84.

How does ADC target HER family in tumor therapy?

(source:internet, reference only)


Disclaimer of medicaltrend.org


Important Note: The information provided is for informational purposes only and should not be considered as medical advice.