Novel Antibody-Drug Conjugate for Treatment of Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC), a type of kidney cancer, is among the 10 most common cancers worldwide. It is estimated that there will be more than 76,080 new cases of RCC annually in the United States alone, with more than 13,780 deaths in 2021. RCC is a highly metastatic disease, which leads to the development of cancer in a secondary and distant location (e.g., lung, bone, and lymph node) in the body. The 5-year survival of metastatic RCC is only 12%. So, no doubt, it is a devastating disease. Over the past decade treatment of RCC has been revolutionized from targeted therapy (e.g., Sunitinib, Bevacizumab), immunotherapy (e.g., Avelumab, Ipilimumab), cytokine-based (high dose of IL-2) therapies, and a combination of them. However, a significant number of patients developing resistance to targeted therapy have evolved over the years. This is known as adoptive resistance of RCC and it is an active field of research. On the other hand, surgery (nephrectomy) is the preferred treatment option for local disease, but one-third of patients relapse following nephrectomy. Therefore, the primary challenge of metastatic RCC remains, i.e., complete response to single-treatment method is rare. Further, excessive and prolonged use of targeted agents is associated with significant toxicities requiring toxicity management. The lack of technologies for specific delivery of drug(s) in tumors has made it challenging to deal with treatment related to target toxicities. Innovation: We propose to use a novel antibody drug conjugate (ADC) technology where anticancer drugs are specifically sent to cancer cells via a cancer cell directing antibody. In the past, efforts to use ADCs for kidney cancer failed due to excessive toxicity observed in phase 1 clinical trials. This stemmed from the inadequate design of antibody and drug conjugation leading to premature release (instability) of the drug in blood, causing the toxic effect. We are uniquely positioned to address the above requirements: (1) We have developed an innovative noncovalent affinity linker technology (MAGNET), which yields stable ADC, and can be engineered using off-the-shelf antibodies in less than 8 minutes. (2) We will use a combination of chemotherapy and targeted therapy drug and deliver it to the specific location by conjugating with an RCC directing antibody. We will use a cytotoxic drug, which is also known to reduce metastatic signaling in RCC, even in very low concentration. Additionally, we will use a targeted therapy, which is capable of blocking multiple signaling pathways (PI3K-mTOR1/2) leading to reduced adoptive resistance (drug resistance) of RCC. We will use Kidney Injury Molecule-1 (KIM-1) and c-Met as targets as they are selectively expressed by > 90% (KIM-1) and 40%-80% (c-Met) of RCC tumors and not expressed in the normal tissue. Our specific aims are: Aim 1: Synthesis and characterization of KIM-1 and c-Met targeted antibody drug conjugate via MAGNET-based plug-and-play strategy. We will use our chemically synthesized bivalent-PEG linkers to connect both drugs simultaneously with cancer cell-targeting antibody. We will fully characterize their physicochemical properties consistent with benchmarks required for clinical translation. Aim 2: We will evaluate the internalization, specificity toward cancer cells in vitro, and toxicity profiles in mice. We ll compare the dual drug-loaded ADCs with single-drug ADCs and IgG control ADC. The ADC that exhibits the highest potency against the cancer cells with lower toxicity against normal cells (i.e., highest therapeutic index) will be evaluated, in vivo, for pharmacokinetics and systemic toxicity profile. Aim 3: The effectiveness of the dual drug-loaded ADC will be screened in RCC-bearing tumor models in mice. We will dissect the efficacy of the dual-loaded ADC vs monotherapy and current standards of care, using mice survival and tumor regression. We will test the ADCs in metastatic and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210619
Entities
People
- Tanmoy Saha
Organizations
- United States Army