Nanoparticulate-based antibody-drug conjugates for targeted lung cancer

Abstract

Nanoparticulate-Based Antibody-Drug Conjugates for Targeted Lung Cancer nanoparticulate-based antibody-drug conjugates (ADCs) for targeted drug delivery, specifically for the treatment of lung cancer. More particularly, the invention involves the use of nanoparticulate carriers to deliver cytotoxic agents conjugated to antibodies targeting specific lung cancer antigens, thereby enhancing the therapeutic efficacy and minimizing systemic toxicity

Description

[0001] FIELD OF INVENTION

[0002] The present invention relates to nanoparticulate-based antibody-drug conjugates (ADCs) for targeted drug delivery, specifically for the treatment of lung cancer. More particularly, the invention involves the use of nanoparticulate carriers to deliver cytotoxic agents conjugated to antibodies targeting specific lung cancer antigens, thereby enhancing the therapeutic efficacy and minimizing systemic toxicity.

[0003] BACKGROUND OF THE INVENTION

[0004] Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Despite advances in early detection and treatment, the prognosis for lung cancer patients, particularly those with non-small cell lung cancer (NSCLC), remains poor. Traditional chemotherapy, while effective in some cases, often leads to severe side effects due to the lack of specificity in targeting cancer cells.

[0005] Antibody-drug conjugates (ADCs) represent a promising strategy for targeted cancer therapy by linking potent cytotoxic agents to monoclonal antibodies (mAbs) that specifically target tumor-associated antigens. However, the clinical use of ADCs has been limited by challenges such as poor stability, inefficient drug release, and non-selective toxicity.

[0006] Nanoparticulate carriers, including liposomes, polymeric nanoparticles, and inorganic nanoparticles, have gained significant attention for their ability to improve the stability, pharmacokinetics, and targeted delivery of drugs. When combined with antibodies, these nanoparticulate carriers can improve the precision of drug delivery to cancer cells, thereby overcoming many of the limitations of traditional ADCs.

[0007] Thus, there is a need for a novel formulation of ADCs utilizing nanoparticulate carriers specifically designed for the treatment of lung cancer, offering enhanced targeting specificity, improved pharmacokinetics, and reduced off-target toxicity. SUMMARY OF PRESENT INVENTION: -

[0008] The present invention provides a nanoparticulate-based antibody-drug conjugate (ADC) for the targeted treatment of lung cancer. The ADC comprises:

[0009] 1. An antibody or antibody fragment or Bispecific or Tri specific antibody that specifically binds to a target antigen expressed on the surface of lung cancer cells.

[0010] 2. A drug payload which is a cytotoxic agent conjugated to the antibody through a nanoparticulate carrier, allowing for targeted delivery and controlled release.

[0011] 3. A nanoparticulate carrier made from biocompatible materials, such as lipids, polymers, or inorganic nanoparticles, that encapsulates the drug payload and facilitates controlled release at the target site.

[0012] In one embodiment, the nanoparticulate carrier may be a lipid-based nanoparticle (liposome), polymeric nanoparticle, or inorganic nanoparticle (e.g., silica or gold nanoparticles). These carriers can enhance the stability, bioavailability, and tumorspecific accumulation of the ADC, improving therapeutic outcomes in lung cancer treatment.

[0013] The invention also provides methods for preparing the ADCs and their use in treating lung cancer, including non-small cell lung cancer (NSCLC).

[0014] DETAILED DESCRIPTION OF THE INVENTION

[0015] Embodiments, of the present disclosure, will now be described with reference to the accompanying drawings.

[0016] 1. Antibodies or Fragments Thereof

[0017] The ADCs described herein include monoclonal antibodies (mAbs) or antibody fragments that specifically bind to tumor-associated antigens expressed on the surface of lung cancer cells. Suitable antibodies include, but are not limited to: EGFR- targeting antibodies: Epidermal growth factor receptor (EGFR) is overexpressed in a significant number of lung cancer cases, particularly in non-small cell lung cancer (NSCLC).

[0018] PD-L1 -targeting antibodies: Programmed cell death ligand 1 (PD-L1) is frequently expressed in both NSCLC and small cell lung cancer (SCLC).

[0019] HER2-targeting antibodies: Human epidermal growth factor receptor 2 (HER2) is overexpressed in some lung cancers.

[0020] VEGFR targeting antibodies :These are specifically designed to bind to VEGFRs, blocking the interaction between VEGF ligands (e.g., VEGF-A, VEGF-B, VEGF-C) and the receptor. This prevents downstream signaling that would otherwise promote angiogenesis uPAR targeting antibodies : These antibodies specifically bind to uPAR and block its interaction with uPA or other binding partners. By targeting uPAR, monoclonal antibodies can inhibit tumor cell invasion and metastasis, as well as reduce the pathological degradation of the extracellular matrix.

[0021] Other tumor-associated antigens Such as CEA (carcinoembryonic antigen), MUC1, and mesothelin.

[0022] The antibody or antibody fragment is selected based on its ability to specifically bind to antigens overexpressed on the surface of lung cancer cells, allowing for selective targeting and delivery of the cytotoxic drug payload.

[0023] 2. Nanoparticulate Carrier

[0024] The nanoparticulate carrier is used to encapsulate the drug payload and conjugate it to the antibody. The carrier is designed to enhance the solubility, stability, and bioavailability of the drug while providing a mechanism for controlled release at the target site. Suitable nanoparticulate carriers include:

[0025] Lipid-based nanoparticles (liposomes): Liposomes are biocompatible and biodegradable carriers that can encapsulate hydrophobic or hydrophilic drugs. Liposomal formulations can improve the stability and circulation time of the ADC.

[0026] Polymeric nanoparticles**: Biodegradable polymeric nanoparticles, such as those based on poly(lactic-co-glycolic acid) (PLGA) and Human serum Albumin, can be engineered to provide controlled release of the drug payload at the tumor site.

[0027] Inorganic nanoparticles: Nanoparticles made from silica, gold, or other biocompatible materials can also be used to deliver the drug payload, with the added advantage of easy surface functionalization for enhanced targeting.

[0028] The nanoparticulate carrier can also include surface modifications such as polyethylene glycol (PEG) or targeting ligands (e.g., peptides or aptamers) that promote the specific binding of the ADC to cancer cells.

[0029] 3. Drug Pay load

[0030] The drug payload is a cytotoxic agent conjugated to the antibody through the nanoparticulate carrier. The drug is selected for its ability to induce cell death or inhibit tumor growth. Examples of suitable pay loads include:

[0031] Cytotoxic Payload selected from list Such as maytansinoids (e.g., DM1), auristatins (e.g., monomethyl auristatin E, MMAE), anthracyclines (e.g., doxorubicin), Cisplatin , Carboplatin , Paclitaxel, Docetaxel , Gemcitabine, Vinorelbine, Pemetrexed, Etoposide , Nab-paclitaxel, Erlotinib, Gefitinib ,Afatinib, Osimertinib,Crizotinib,Ceritinib,Alectinib,Brigatinib,Lorlatinib ,Crizotinib,Entrectinib,Repotrectinib,Dabrafenib,Trametinib,Capmatinib,Tepotinib,Larotrecti nib,Entrectinib,Selpercatinib,Pralsetinib,Sotorasib,Adagrasib,Mobocertinib,Biatinib,Ensartini b,Sotorasib,adgarsib,MRTX849,Trametinib,ganetespib,

[0032] The drug is conjugated to the antibody via the nanoparticulate carrier, ensuring stability during circulation and targeted release at the tumor site.

[0033] Conjugation Strategy

[0034] The antibody and drug payload are conjugated through a covalent bond, typically via a cleavable linker. The linker is designed to remain stable in the bloodstream and release the drug payload upon internalization by the target cell. Suitable linkers include:

[0035] Disulfide linkers: Cleavable in the reducing environment of the tumor cell. Peptide linkers Sensitive to specific enzymes or acidic pH conditions found in the tumor microenvironment.

[0036] The conjugation strategy ensures that the drug is only released after the ADC has bound to the target antigen on the surface of the cancer cell, minimizing off-target effects.

[0037] Targeting and Release Mechanism

[0038] The nanoparticulate-based ADCs are designed to exploit both passive targeting (through the enhanced permeability and retention effect) and active targeting (through receptor-mediated endocytosis) for efficient drug delivery. After binding to the target antigen on the cancer cell surface, the ADC is internalized into the cell, where the nanoparticulate carrier facilitates the controlled release of the drug payload, leading to cell death.

[0039] Advantages of the Invention

[0040] 1. Targeted Delivery : By conjugating a potent cytotoxic agent to a monoclonal antibody that specifically binds to lung cancer cells, the ADC allows for precise targeting of cancer cells, reducing damage to healthy tissue.

[0041] 2. Improved Pharmacokinetics: Nanoparticulate carriers enhance the stability and circulation time of the ADC, allowing for prolonged drug exposure to the tumor.

[0042] 3. Controlled Drug Release : The nanoparticulate carrier enables controlled release of the drug payload upon internalization by the target cells, improving the therapeutic efficacy.

[0043] 4. Reduced Systemic Toxicity: By ensuring that the drug is released primarily at the target site, the ADC reduces systemic toxicity and side effects typically associated with conventional chemotherapy.

Claims

CLAIMS,We Claims

1. An antibody-drug conjugate (ADC) for targeted lung cancer treatment, comprising:- an antibody or antibody fragment that specifically binds to a target antigen expressed on lung cancer cells; and- a drug payload conjugated to the antibody via a nanoparticulate carrier, wherein the nanoparticulate carrier is selected from the group consisting of lipid-based nanoparticles, polymeric nanoparticles, and inorganic nanoparticles.