Clinical-stage biopharmaceutical company Himalaya Therapeutics, focused on development and commercialization in Greater China, of a novel class of investigational antibody therapeutics for the treatment of solid tumor cancer, which are based on the Conditionally Active Biologics or CAB technology platform, confirmed the registration of its new office in Shanghai, China.[1]

Himalaya was founded with the exclusive rights from BioAtla to develop and commercialize several specific CAB candidates for the Greater China market of the PRC, Hong Kong, Macau, and Taiwan, including two Phase 1/2 clinical-stage assets, as well as worldwide rights to two additional preclinical drug candidates.

Conditionally Active Biologics
CAB antibodies are innovative, differentiated therapeutics. They are selective and bind reversibly only to targets on tumor cells, and not on normal cells, thereby widening the therapeutic window. In non-human primate and patient studies to date, CAB antibodies have demonstrated high safety with higher potency.

Conditionally Active Biologic proteins are generated using proprietary protein discovery, evolution, and expression technologies. These proteins can be monoclonal antibodies, enzymes, and other proteins designed with functions dependent on changes in microphysiological conditions (e.g., pH level, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells.

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Studies have shown that cancerous tumors create highly specific conditions at their site that are not present in normal tissue. These cancerous microenvironments are primarily a result of the well understood unique glycolytic metabolism associated with cancer cells, referred to as the Warburg Effect.

CAB proteins are designed to deliver their therapeutic payload and/or recruit the immune response in specific and selected locations and conditions within the body and to be active only in the presence of a particular cellular microenvironment. In addition, the activation is designed to be reversible to repeatedly switch ‘on and off’ should the CAB move from a diseased to a normal cellular microenvironment and vice versa.

Pipeline
Himalaya is advancing a pipeline of multiple CAB antibodies, licensed exclusively from BioAtla. The pipeline includes two Phase 1/2 clinical stage agents, CAB-AXL-ADC and CAB-ROR2-ADC, and three preclinical stage CAB antibody cancer therapeutics.

AXL
The AXL receptor tyrosine kinase is highly expressed in certain cancers. AXL appears to sustain resistance to anticancer therapies including chemotherapy, targeted therapy, and immune checkpoint inhibitors. CAB-AXL-ADC is an anti-AXL humanized monoclonal antibody conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB-AXL-ADC) and specifically binds to AXL under conditions found within the tumor microenvironment.[2]

ROR2
CAB-ROR2-ADC is a novel conditionally active ROR2-targeted antibody-drug conjugate. The ROR2 transmembrane protein tyrosine kinase belongs to the ROR subfamily of cell surface receptors and is an onco-fetal protein that acts as a non-canonical Wnt 5A receptor. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development.

ROR2 is found to be highly expressed during embryonic development and in several important cancer types, and the level of expression in tumors is tightly correlated with patient prognosis. Recently, ROR2 and its ligand Wnt 5A have been shown to be induced in cancers that are resistant to treatment with immune checkpoint inhibitors such as anti-PD-1 antibody immune therapy suggesting a mechanistic role of this receptor-ligand axis in resistance to standard cancer treatments resulting in relapsing, minimal residual disease.

However, low to moderate levels of expression of ROR2 in multiple normal adult tissues are predicted based on RNA expression, histological analysis and functional studies. To minimize the risk of potential disruption of normal function of ROR2 receptors on normal cells, BioAtla applies its proprietary CAB technology to develop its CAB antibody-drug conjugate (ADC) targeting ROR2 with the intent to activate binding to the ROR2 receptor only in the tumor microenvironment and deliver the toxic payload to the cancerous cells. The CAB-ROR2-ADC BA3021 is designed to maximize efficacy on ROR2 expressing tumors while minimizing toxicity, leading to better clinical outcomes.

Out-license agreement
In 2019, the company achieved its first exclusive out-license of one of the company’s preclinical stage drugs, CAB-CTLA4, with Beigene and BioAtla for the greater China territory. As part of this agreement, the company is eligible to receive development and commercial milestones, as well as royalties from product sales. CAB-CTLA4 has the potential to enhance the efficacy of one of the few validated combination checkpoint inhibitor therapies, together with Beigene’s leading PD-1 drug candidate, as well as for improved monotherapy treatment in selected cancers.

Development in China
“Himalaya continues to ramp up its physical presence in Mainland China. Recently, we have been growing our clinical staff and working through several high-quality CROs.  Having our new offices in Shanghai will further pave the way for smooth execution of our strategy” said Brian Zhang, Himalaya’s Chief Executive Officer.

“I look forward to moving from San Diego, USA to Shanghai full-time now to join our team on the ground in Shanghai, including Dr. Howe Li, our Chief Medical Officer,” Zhang concluded.

Clinical Trials
CAB-AXL-ADC Safety and Efficacy Study in Adult and Adolescent Patients With Solid Tumors – NCT03425279
CAB-ROR2-ADC Safety and Efficacy Study in Patients With Solid Tumors – NCT03504488

Reference
[1] What are Conditionally Active Biologics (CABs)? ADC Review | Journal of Antibody-drug Conjugates [Article]
[2] Ahnert JR, Taylor MH, O’Reilly EM, Zhang J, Doebele RC, Ben Y, Sharp LL, Boyle JW, et al. BurrisA phase 1/2 dose-escalation and expansion study of a conditionally active anti-AXL humanized monoclonal antibody (BA3011) in patients with advanced solid tumors. Journal of Clinical Oncology 2018 36:15_suppl, TPS12126-TPS12126

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