KN035(Envafolimab)* 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 : Crystal Structure
Current PD-(L)1 therapies in the market require frequent intravenous administration, a major challenge to patient compliance and convenience. Furthermore, there is a growing population of cancer patients who need more user-friendly PD-(L)1 therapies:
KN035 is expected to be 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. The BLA of KN035 has been accepted by NMPA and granted priority review.
AACR 2021：ENVASARC: A Pivotal Trial Of Envafolimab, And Envafolimab In Combination With Ipilimumab, In Patients With Advanced Or Metastatic Undifferentiated Pleomorphic Sarcoma Or Myxofibrosarcoma Who Have Progressed On Prior Chemotherapy
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. The preclinical and clinical trial results of KN046 have shown promising efficacy and significantly reduced toxicity to human peripheral system, with the potential to become the cornerstone of the next generation of the immuno-oncology therapy.
KN046 : Crystal Structure
There are about 20 clinical trials of KN046 in different stages covering more than 10 types of tumors including NSCLC, TNBC, ESCC, HCC and pancreatic cancer in Australia and China. The results of these clinical trials have shown a preliminary profile of good safety and promising efficacy. Alphamab has received FDA clearance to enter phase II trial of KN046 based on the clinical results in China and Australia. Four registrational clinical trials are currently being conducted.
ESMO 2021 poster：KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in combination with Lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): preliminary efficacy and safety results of a prospective phase II trial
ESMO 2021 poster：KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in combination with Platinum doublet chemotherapy as first-line (1L) treatment in patients with advanced NSCLC harboring resistant oncogenic driver alterations
ASCO 2021 poster：A phase 2, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of KN046 in combination with chemotherapy in subjects with advanced non-small cell lung cancer
AACR 2021 poster：Preliminary Safety, Tolerability and Efficacy Results of KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in combination with Nab-paclitaxel in Metastatic Triple-negative Breast Cancer (mTNBC)
KN026* is an anti-HER2 bispecific antibody developed 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. In pre-clinical studies, KN026 has demonstrated potentially equivalent or superior efficacy compared with Trastuzumab and Pertuzumab alone or 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 : Crystal Structure
KN026 received IND approval from the National Medical Products Administration (NMPA) of China and U.S. Food and Drug Administration (FDA) in 2018. Currently, it is in multiple phase I/II clinical trials in China and phase I clinical trial in the United States.
The results of Phase I clinical trials show KN026 has excellent safety, tolerance and potentially superior anti-tumor activity in HER2-positive breast cancer patients who progressed after multiple lines of anti-HER2 treatment.
The therapeutic effect of HER2 targeted therapy depends on the body's adaptive immune response. Therefore, the combination of immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4 can synergistically enhance the anti-tumor effect of HER2 therapies. The combination of HER2 targeted drugs and PD-1 antibody has shown great efficacy in HER2-positive breast cancer and gastric cancer, including a phase 2 trial of triple combination regimen (pembrolizumab,trastuzumab,and chemotherapy) as first-line therapy for HER2-positive metastatic gastric cancer showing 91% ORR,13.0 months median PFS and 27.3 months median overall survival. The phase Ⅲ trial of this triple combination regimen (KEYNOTE-811 study) is ongoing.
KN026 and KN046 have shown good safety, tolerability and anti-tumor efficacy in mono-drug clinical trials. The combination of KN026 plus KN046 demonstrated preliminary good efficacy, safety, and tolerability in an open label, multi-center clinical study in patients with advanced HER2-expressing solid tumors and have failed the standard of care treatment.The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to KN026 in combination with KN046 for the treatment of HER2-positive or low expressing gastric or gastroesophageal junction cancer. SEARCH-01 is an phaseⅡ registration clinical study to evaluate the efficacy, safety and tolerability of KN026 in combination with KN046 for HER2-positive solid tumors. This study is planned to be conducted in 20-30 clinical centers in China and 10-20 US clinical centers with advanced HER2-positive solid tumors, including HER2-positive gastric and gastroesophageal junction cancer etc.
ESMO 2021 poster：Preliminary Efficacy and Safety Results of KN026 (a HER2-targeted Bispecific Antibody) in Combination with KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in Patients (pts) with HER2-positive Gastrointestinal Tumors
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.