From June 25-27, 2024, World ADC Asia 2024 was held in Incheon, South Korea. Henlius made its big debut at the World ADC Event Series and showcased its multiple Antibody Drug Conjugate (ADC) products as well as self-developed ADC technical platform Hanjugator™. Meanwhile, the company’s impressive display at booth #2 attracted great attention of the visitors and engaged potential innovative collaboration.

During the conference, Dr. Yongqiang Shan, General Manager of Henlius Global Innovation Center, delivered a keynote speech around the theme of “From Product to Platform: Henlius’ Practices & Progress in ADC to Address Unmet Medical Needs”, conducted wide-raging discussions with players from global research institutes and biopharmaceutical companies in ADC drug development.

As an innovative global biopharma company, Henlius actively explores the new target and mechanisms guided by clinical needs, continuously expanding its product portfolio in terms of therapeautic areas and modalities. Based on its competitive edge of an integrated antibody drug R&D platform, Henlius accelerated the development of ADC and targeted drug conjugates. Two potential first-in-class/best-in-class innovative ADC candidates, HLX42, an EGFR-targeting ADC and HLX43, a PD-L1-targeting ADC, have exhibited good anti-tumor efficacy and safety profile in preclinical studies. As of now, the two products have been approved for conducting clinical trial by the National Medical Products Administration (NMPA) and U.S. Food and Drug Administration (FDA), and phase 1 clinical trials were conducted in China. HLX42 was also granted Fast Track Designation (FTD) by the U.S. FDA, for the treatment of patients with advanced or metastatic EGFR-mutated non-small cell lung cancer whose disease has progressed on a 3rd-generation EGFR tyrosine kinase inhibitor (TKI). 

In addition, Henlius has built a diversified ADC product pipeline, with differentiated-developed candidates under preclinical development. Hanjugator^TM, the antibody and linker-payload modular toolbox with independent intellectual property, has been established by the company to develop differentiated and clinically valuable ADC products, continually improving ADC’s potency, selectivity, safety and therapeutic window, expanding ADC’s indication application.

Moreover, updated results from the preclinical studies of HLX42 and HLX43 were released as poster presentations. The exhibition details are as follows:  

Preclinical study results of HLX42

Title

HLX42, a Novel EGFR-Targeting ADC, for Cetuximab or TKI Resistant Cancer

Background

EGFR is highly expressed in multiple types of solid tumors. And its aberrant expression is well recognized as a driving force in tumorigenesis and disease progression. Despite the great success of monoclonal antibody targeting EGFR and 3rd generation receptor TKIs, there is still a significant unmet medical need for effective therapies for patients who are refractory to current therapies or relapse after standard of care. ADC targeting EGFR has entered the clinical stage and shown an acceptable safety profile and preliminary clinical activity. However, conventional EGFR ADCs may be associated with significant treatment-related toxicities since EGFR is broadly expressed in normal epithelial tissues.

HLX42 is a next-generation EGFR-targeting ADC, comprised of a high-affinity humanized IgG1 antibody targeting EGFR, conjugated to a novel topoisomerase-I inhibitor payload whose cleavage and release are tumor microenvironment dependent and do not require internalization by tumor cells into lysosomes. This unique mechanism of tumor microenvironment activation and payload release allows HLX42 to possess a higher therapeutic index and better safety profile. 

Methods

HLX42 was examined in antigen binding, internalization and plasma stability assays; efficacy analyses were performed in CDX and PDX models of non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC).

Results

• In vitro analyses demonstrated that HLX42 possessed similar affinity and internalization rate compared to parental antibody (HLX07), and it was stable in the plasma of rats, cynomolgus monkeys and humans. 

• In in vivo studies, HLX42 showed potent tumor suppression in several CDX and PDX models that were resistant to Cetuximab or EGFR TKIs or anti-PD-1 antibody. In the NCI-H1993 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks resulted in 91.5% TGI compared to 79.8% TGI when treated with anti-EGFR-GGFGDxd. Similarly, in the EBC-1 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks eradicated all lesions. All mice remained tumor free 24 days after the last dose, while tumor began to regrow in the anti-EGFR-vc-MMAE treated group. Furthermore, in the LU3075 PDX model which poorly responded to Osimertinib monotherapy, HLX42 eradicated all lesions.In another PDX model harboring EGFR exon19 deletion/T790M/C797S mutations, which exhibited complete tolerance to Osimertinib, a single dose treatment resulted in significantly complete response. After 4-week treatment in this PDX, the TGI of the IgG-linker-payload 8 mpk group was 58.1%, indicating the tumor microenvironment-specific lysis of linker-payload. HLX42 also showed strong efficacy in HT29 CRC CDX model and Cetuximab and/or anti-PD-1 resistant microsatellite stable (MSS) mCRC PDX model. In toxicology studies conducted in rats and non-human primates, HLX42 had favorable safety profile. 

Conclusions

Taken together, these data strongly suggest that HLX42 is a highly promising ADC product with great clinical potential for the treatment of advanced/metastatic NSCLC and mCRC patients who failed from standard treatments which has urgent unmet medical needs.

Preclinical study results of HLX43

Title

HLX43, a PD-L1-Targeting ADC, for Cancer Resistant to PD-1/PD-L1 Blockade

Background

PD-1/PD-L1 monoclonal antibodies, as the most successful immune checkpoint inhibitors, have revolutionized the treatment of cancer. However, there are still many patients with positive PD-L1 expression who do not respond to or develop resistance to PD-1/PD-L1-targeted therapy. The favorable expression of PD-L1 in tumors makes it an attractive target for ADC development, which might alter the treatment for PD-1/PD-L1 inhibitor refractory/resistant (R/R) cancers.

HLX43 is a PD-L1-targeting ADC, composed of an engineered version of the anti-PD-L1 humanized IgG1 antibody (HLX20), conjugated via a next-generation linker to a camptothecin-based toxin. The drug to antibody ratio is around 8. This novel linker-payload is preferentially activated for cleavage in the tumor microenvironment. And the tumor-specific release of the toxin is independent of the internalization of the ADC. This unique mechanism of action can efficiently deliver toxin into PD-L1-expressing malignant cells, while sparing the normal cells, which will greatly reduce the systemic toxicity associated with the non-specific release of toxin in the periphery. 

Methods

HLX43 was examined in antigen binding, internalization, plasma stability and immunotoxicity assays. In vivo efficacy studies were performed in breast cancer CDX and PDX models from non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC).

Results

• In vitro studies demonstrated that HLX43 possessed similar affinity and internalization rate compared to parental antibody, and it showed good stability in the plasma of rats, cynomolgus monkeys and humans. HLX43 shows no immunotoxicity towards PD-L1 positive human APCs. 

• In in vivo efficacy studies, HLX43 induced tumor regression in multiple PDX models, and was well tolerated, with no changes in body weight compared to control animals across all dosing groups. In the MDA-MB-231 CDX model, weekly administration of HLX43 for three times induced significant tumor regression and superior anticancer efficacy over the anti-PD-L1-GGFG-Dxd and anti-PD-L1-vc-MMAE at equivalent doses, while no body weight loss was observed. In the NSCLC PDX model, weekly administration of HLX43 for three times, HLX43 caused obvious regression of tumors. Even after stopping treatment for 3 weeks, HLX43 at 8 mg/kg groups still had durable response in lesions. After 3-week treatment in this PDX, the TGI of the IgG-linker-payload 8 mpk group was 61.6%, indicating the tumor microenvironment-specific lysis of linker-payload. HLX43 also induced significant tumor regression in HCC PDX model with (IHC1+) or without (IHC-) PD-L1 expression, meanwhile showed strong synergy with anti-VEGF antibody. In the toxicology studies in mice and cynomolgus monkeys, HLX43 was well tolerated in both species. 

Conclusions

Taken together, these data strongly suggest that HLX43 is a highly promising ADC product with great clinical potential for treatment of advanced/metastatic solid tumors, especially for advanced/metastatic NSCLC and HCC patients with disease progression on standard treatments, which has urgent unmet medical needs.