Anti-huLRRC15 Antibody Drug Conjugates for Tumor Microenvironment Targeting
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Solution Overview
Problem
Current cancer therapies face challenges such as lack of selectivity towards cancer cells, development of resistance, and the immunosuppressive tumor microenvironment, which limits their effectiveness in targeting cancer cells effectively.
Innovation Solution
Development of anti-huLRRC15 antibody drug conjugates (ADCs) that specifically target the extracellular domain of human leucine-rich repeat-containing protein 15 (huLRRC15) expressed on cancer-associated fibroblasts, using cytotoxic agents linked to antibodies via linkers, which can bind to the shed portion of huLRRC15, exerting potent antitumor effects by a targeted bystander killing effect.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used to treat cancer, then cancer cells can be killed, but normal healthy cells are also damaged and resistance develops
Solution Approach 1:
The therapy is segmented into two distinct components: an antibody component that specifically recognizes and binds to tumor-associated fibroblasts (TAFs) expressing LRRC15, and a cytotoxic payload component that delivers the killing effect. This segmentation ensures that the cytotoxic agent is delivered specifically to the target cells through the selective binding of the antibody, thereby sparing normal cells from direct exposure and damage.
Solution Approach 2:
The antibody acts as an intermediary that mediates between the cytotoxic payload and the target cells. The antibody specifically binds to LRRC15 on TAFs, serving as a selective delivery vehicle that transports the cytotoxic agent precisely to the tumor microenvironment. This intermediary mechanism ensures selective targeting while minimizing off-target effects on normal healthy cells.
2Object-affected harmful factors
If targeted therapeutics are used to interfere with cellular processes of cancer cells, then side effects are reduced, but treatment resistance still develops
Solution Approach 1:
Instead of directly targeting cancer cells with conventional therapeutics, this invention inverts the approach by targeting the tumor-associated fibroblasts (TAFs) in the tumor microenvironment that support cancer cell survival and promote resistance. By eliminating the protective stromal compartment through LRRC15-targeted ADC therapy, cancer cells become more vulnerable to treatment, thereby overcoming resistance mechanisms while maintaining reduced side effects.
3Reliability
If fibroblasts in the tumor microenvironment are present, then they form a barrier preventing cancer drugs from reaching cancer cells, but targeting these fibroblasts requires high specificity
Solution Approach 1:
The antibody is engineered with specific affinity for LRRC15, a protein highly expressed on tumor-associated fibroblasts within the tumor microenvironment but absent or minimally expressed on normal fibroblasts. This local quality distinction in protein expression enables highly selective targeting of the tumor stroma, allowing precise delivery of the cytotoxic payload to the tumor site while sparing normal tissues from off-target effects.
Data Source
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AI summary
The present disclosure provides antibodies, antibody binding fragments, and antibody drug conjugates that bind human LRRC15, their methods of making, and their uses to treat patients having cancer.