Envafolimab(KN035)* is an investigational PD-L1 antibody currently being evaluated in broad clinical studies in the US, China, and Japan. It is created by a fusion of the of PD-L1 domain antibody with the Fc domain of a regular antibody. Compared with conventional PD-(L)1 antibodies currently approved and under development, KN035’s unique design makes a differentiated and competitive profile: better tumor tissue penetration in animal model studies, subcutaneous injectable, high affinity and stability, low immunogenicity, mutated Fc domain to eliminate ADCC/CDC activity, and comparable in vivo half-life.

KN035 is the first approved subcutaneous PD-L1 antibody therapeutics, on the market. It can be injected easily without the need for intravenous (IV) injection, therefore significantly shortens the administration time. KN035 has the potential for home-based use, which will be more convenient use for tumor patients and improve the quality of life for patients. KN035 has obtained the U.S. FDA's orphan drug designation for advanced biliary tract cancer.

KN046 is the world's first recombinant humanized PD-L1/CTLA-4 bispecific antibody independently developed by Jiangsu Alphamab. Its innovative designs include: a proprietary CTLA-4 domain antibody with a significantly improved safety profile; a bispecific antibody fused with PD-L1 antibody; engineered to target the tumor microenvironment with high PD-L1 expression, and Treg clearing function.

There are about 20 clinical trials of KN046 in different stages covering more than 10 types of tumors including NSCLC, pancreatic cancer, thymic cancer, HCC, ESCC and TNBC in Australia, the US and China. The results of these clinical trials have shown an advantage in survival for patients. Alphamab Oncology has received FDA clearance to enter phase II trial of KN046 based on the clinical results in China and Australia. Moreover, KN046 has obtained the U.S. FDA's orphan drug designation for thymic epithelial tumor in September 2020. Four pivotal clinical trials are currently being conducted, among which the interim analysis of the phase III clinical study of KN046 combined with chemotherapy as the first-line treatment of NSCLC successfully met the prespecified PFS endpoint.

KN026* is an anti-HER2 bispecific antibody invented by Alphamab Oncology using the proprietary Fc-based heterodimer bispecific platform technology called CRIB (Charge Repulsion Induced Bispecific). KN026 can bind two non-overlapping epitopes of HER2 simultaneously, leading to a dual HER2 signal blockade. KN026 has demonstrated superior efficacy compared with Trastuzumab and Pertuzumab in combination, such as increased binding affinity, as well as better tumor inhibition in HER2-positive tumor cell lines. Additionally, KN026 has also shown inhibitory effect on tumor cells with medium or low HER2 expression or Trastuzumab-resistant cell lines.

KN026 received IND approval from the National Medical Products Administration (NMPA) of China and U.S. Food and Drug Administration (FDA) in 2018. Currently, a number of clinical trials are underway in China and the United States, including breast cancer, gastric cancer/gastroesophageal junction cancer, etc. Two registration clinical studies of KN026 combined with chemotherapy and KN026 combined with KN046 without chemotherapy in the treatment of gastric cancer are in progress.

The results of prior clinical studies showed that KN026 has good efficacy and safety profiles, even in heavily pretreated patients with HER2-positive breast cancer..

KN019 is a biosimilar of Belatacept (Nulojix®), an immunosuppressive agent approved for prophylaxis of organ rejection in adult patients receiving a kidney transplant. As a fusion protein composed of the Fc-fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, Belatacept acts as a selective T cell co-stimulation blocker. Belatacept’s superior efficacy profile has been demonstrated in long-term outcome studies*.

Belatacept is an improved version of Abatacept (Orencia®) with higher potency. Orencia is approved for rheumatoid arthritis, idiopathic arthritis, and psoriatic arthritis, and it achieved global sales of about US$2.7 billion in 2017.

KN019 has started phase II trial for rheumatoid arthritis in August 2019 and will expand to oncology-related indications in the future.

Due to its structure of a fusion protein with complex glycosylation, Belatacept is very difficult to manufacture as the biosimilar product. So far, few companies are able to develop a competitive biosimilar of Belatacept. In contrast, KN019 has demonstrated robust CMC and superior quality in multiple batches of large-scale production.

KN052 is a PD-L1/OX40 bispecific antibody developed by Alphamab Oncology using the company's bispecific antibody platform. It can simultaneously bind PD-L1 and OX40, effectively reversing tumor induced immune inhibition by blocking the PD-L1/PD-1 pathway and promoting the immune response by agonizing OX40. KN052 prevents the immune escape of tumor cell, on the other hand, it activates CTL T cells and attenuates Treg-mediated immunosuppression. Through synergistic mechanisms, KN052 is expected to exert strong antitumor efficacy.

PD-L1 antagonist and OX40 agonist activity in one molecule；tandem structure for antigen binding domain arrangement to attenuate anti-OX40 toxicity；wildtype IgG1 Fc with full Fc function to enable depletion of Tregs overexpression OX40. OX40 is a member of key class of T cell costimulatory molecules. OX40, through interaction with OX40L, plays key role in survival and amplification of effector T cells and memory T cells and induce cytokine secretion. It can be used as an adjuvant in combination with tumor vaccines and cell therapy.

In preclinical studies, KN052 showed significantly stronger activity than single antibody or in combination. In February 2022, the IND for KN052 was approved by the National Medical Products Administration (NMPA) to initiate Phase I clinical trials in China. The first patient was dosed in the KN052-CHN-001 PhaseⅠtrial of KN052 in June 2022.

JSKN003 is an anti-HER2 bispecific antibody-drug conjugate (ADC), which is developed inhouse with proprietary Glycan-specific conjugation platform. Through enzyme catalysis and click chemistry, the payloads are site-specifically linked to glycan on Fc. The glycan structure is precisely controlled via process engineering which renders consistent DAR with more favorable stability. Upon binding with HER2, JSKN003 induces clustering of the receptor and triggers extensive internalization the JSKN003-Her2 complex. The internalization leads to release of payload that kills tumor directly or via and by stander effect.

Comparing with other ADC drugs, JSKN003 induces faster and more intense endocytosis , which leads to stronger bystander effect in HER2-expressing tumors. Meanwhile the better serum stability ensures much wider therapeutic window. For example, JSKN003 shows better safety profile in preclinical study and similar tumor killing activity with Enhertu (DS-8201) in both high and low HER2 expression model (CDX+PDX).