The Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor 3 (HER3) are both members of ErbB/HER receptor tyrosine kinase (RTK) family, which are expressed in several types of tumors [1], including metastatic gastrointestinal tumors [2] and other solid tumor, including breast [3], ovarian [4][5], lung [6], colorectal [7], pancreatic [8], melanoma [9], and head and neck [10] and prostate cancers.[11] Due to their their over-expression and pathway dependence in common human epithelial carcinoma tumors, EGFR and HER2 are targeted in cancer therapy. [12]

Researchers at SystImmune, in collaboration with their partners at Sichuan Baili Pharmaceutical, developed BL-B01D1, a novel EGFR×HER3-targeting Antibody-drug Conjugate (ADC) which binds to EGFR and/or HER3 positive cells and is expected to be superior to currently approved and commercially available anti-EGFR and anti-HER3 ADCs.

The tetravalent BL-B01D1 ADC consists of the bispecific antibody izalontamab* (previously known as SI-B001), which targets EGFR/HER3, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (ED-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. Using a highly stable linker, BL-B01D1 achieves a drug-to-antibody-ratio (DAR) of 8.

BL-B01D1 blocks EGFR and HER3 signals to cancer cells, reducing proliferation and survival signals. Upon antibody mediated internalization, BL-B01D1 is trafficked to cancer cell lysosomes and liberates its therapeutic payload that induced genotoxic stress activating pathways leading to cancer cell death.

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In xenograft models, composed of either the human colorectal cancer cell line SW620 or pancreatic cancer cell line BxPC3, researchers evaluated the pharmacological potential of BL-B01D1.

The results demonstrated tumor inhibition activity of BL-B01D1 which were compared with ADCs prepared from each parental anti-EGFR or anti-HER3 antibody conjugated with the same linker and payload. The bispecific ADC, BL-B01D1 exhibited stronger tumor inhibition capacity than the anti-EGFR ADC and the anti-HER3 ADC separately.

The results from the preclinical studies seem to suggest that BL-B01D1, as an EGFR×HER3-targeting ADC, may be a promising novel agent with activity to treat a broad range of human cancers.

In ongoing phase 1a clinical studies investigators are evaluating the safety and tolerability of BL-B01D1 in patients with locally advanced or metastatic urinary tumors and other solid tumors will be investigated to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) of BL-B01D1. Safety and tolerability of BL-B01D1 and, in addition, the preliminary efficacy, pharmacokinetic characteristics, and immunogenicity of the investigational drug in patients with locally advanced or metastatic urinary tumors and other solid tumors will be used to determine recommended phase 2 dose (RP2D) for planned phase 2 clinical studies

The available phase 1 data shows that BL-B01D1 exhibit excellent efficacy but low levels of targeted toxicity in the non-small cell lung cancer (NSCLC) treatment setting. Based on these initial outcomes BL-B01D1 the researchers believe that the investigational agent has the potential, as a novel, efficacious therapeutic agent for the treatment of NSCLC.  They believe that BL-B01D1 may have a similar therapeutic impact as trastuzumab deruxtecan (DS-8201a; Enhertu; Daiichi Sankyo and AstraZeneca), a HER2 targeting ADC, has in the treatment of breast cancer.

What to expect at ASCO 2023
During the annual meeting of the American Society of Clinical Oncology (ASCO), to be held in Chicago, June 2 – 6, 2023, results from early-stage clinical trials of BL-B01D1, the bi-specific antibody-drug conjugate (ADC) targeting EGFR and HER3, will be presented. In addition, results from Phase 2 clinical trials of izalontamab, the bi-specific antibody targeting EGFR and HER3, and the design and rationale of the trial in progress of the first tetra-specific T-cell engager, emfizatamab, will be presented.

“Through our commitment to innovative research, we are pleased to have multiple modalities selected to showcase our groundbreaking pipeline at this year’s ASCO meeting. Our focus on advancing the field of oncology is reflected in the clinical data that our distinguished clinical investigators will present, and we are excited to share our progress toward improving patient outcomes with the scientific community,” noted Yi Zhu, Ph.D., President & Chief Executive Officer of SystImmune.

“We are thrilled to be presenting our clinical data at the upcoming ASCO Annual Meeting, which includes our first-in-class bi-specific antibody-drug conjugate. The results of our trials highlight the potential of our innovative therapies to address unmet needs in a variety of solid tumor types. At SystImmune, we remain committed to advancing the field of oncology and expanding treatment options to benefit patients,” added Martin Olivo, M.D., Chief Medical Officer of SystImmune.

Key highlights of data selected by ASCO
Molecule NameAbstract Title Abstract Number / Presentation Details  
BL-B01D1BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study.Abstract #3001
Oral Presentation:
Monday, June 5, 8:00 -11:00 am CDT
SI-B001SI-B001 plus chemotherapy in patients with locally advanced or metastatic EGFR/ALK wild-type non-small cell lung cancer: A phase II, multicenter, open-label study.Abstract #9025
Poster Discussion Session
Poster Available:
Sunday, June 4, 8:00 – 11:00 am CDT
Sunday, June 4, 4:30 – 6:00 pm CDT
SI-B001Results from two phase II studies of SI-B001, an EGFR×HER3 bispecific antibody, with/without chemotherapy in patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC).Abstract #6037
Poster Available:
Monday, June 5, 1:15 – 4:15 pm CDT

GNC-038, A tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale.

Abstract #TPS2668
Poster Available:
Saturday, June 3, 8:00 -11:00 am CDT
SI-B003SI-B003 (PD-1/CTLA-4) in patients with advanced solid tumors: A phase I study.Abstract #e14668


Note: * Izalontamab, an EGFR×HER3 bispecific antibody that can target both EGFR and HER3 is built on a tetravalent platform having two binding domains for distinct Growth Factor Receptors that drive cancer cell proliferation and survival. As part of the primary mechanism of action, izalontamab blocks EGFR and HER3 signals to cancer cells,  As part of a secondary process, izalontamab, mediates the innate immune effector functions toward cancer cells through a wt FC receptor.

Clinical trials
A Study of BL-B01D1 in Patients With Locally Advanced or Metastatic Urological Tumors and Other Solid Tumors – NCT05393427
A Clinical Study of BL-B01D1 in Patients With Multiple Solid Tumors Such as Locally Advanced or Metastatic Urinary System Tumors – NCT05785039
A Clinical Study of BL-B01D1 in Patients With Multiple Solid Tumors Such as Recurrent or Metastatic Gynecological Malignancies – NCT05803018
A Study of BL-B01D1 in Patients With Unresectable Locally Advanced or Metastatic Breast Cancer and Other Solid Tumors – NCT05470348

Highlights of prescribing information
Trastuzumab deruxtecan (DS-8201a; Enhertu; Daiichi Sankyo and AstraZeneca) [Prescribing Information]

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[2] Slesak B, Harlozinska A, Porebska I, Bojarowski T, Lapinska J, Rzeszutko M, Wojnar A. Expression of epidermal growth factor receptor family proteins (EGFR, c-erbB-2 and c-erbB-3) in gastric cancer and chronic gastritis. Anticancer Res. 1998 Jul-Aug;18(4A):2727-32. PMID: 9703936.
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[6] Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M, Cagle PT. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol. 1997 Feb;10(2):142-8. PMID: 9127320.
[7] Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD, Garrigues J, Radke S, Todaro GJ, Salomon DS. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7792-6. doi: 10.1073/pnas.88.17.7792. PMID: 1715580; PMCID: PMC52389.
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[9] Reschke M, Mihic-Probst D, van der Horst EH, Knyazev P, Wild PJ, Hutterer M, Meyer S, Dummer R, Moch H, Ullrich A. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res. 2008 Aug 15;14(16):5188-97. doi: 10.1158/1078-0432.CCR-08-0186. PMID: 18698037.
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DOI: 10.1158/1538-7445.AM2023-2642

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