Development of Biparatopic CXCR4-targeted Bispecific ADCs

Antibody-drug conjugate (ADC) is becoming an attractive cancer therapeutic strategy that combines the unique targeting capabilities of monoclonal antibodies (mAbs) with the specific cancer killing ability of cytotoxic drugs. At the same time, the bispecific antibody (bsAb) as a growing class of immunotherapies continues to show significant and impressive therapeutic value. Recently, the combination of ADC and bsAb to form a novel therapeutic format named bispecific ADC is under active development and evaluation.

Creative Biolabs brings together the most renowned ADCs experts and long standing experience in antibody development to offer the best-in-class bispecific ADC development services. At present, we provide the novel bispecific biparatopic ADC design and construction service from optimized antibody selection to final conjugate characterization.

Introduction of CXCR4

CXCR4 also known as fusin or CD184 is a chemokine receptor protein that is encoded by the CXCR4 gene in humans. It belongs to the large superfamily of G protein-coupled receptors possessing seven-transmembrane helices that interacts with its endogenous ligand, CXCL12 (SDF-1α). CXCR4 functions in a variety of biological processes, such as the trafficking and homeostasis of immune cells (such as T lymphocytes). CXCR4 is also highly expressed on many cancer cells that play important roles in tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. Therefore, CXCR4 has been considered to be a prognostic marker in various types of cancer, including leukemia, breast cancer, and prostate cancer. Besides, CXCR4 is highly expressed in cancer metastasis that can result in enhanced signaling. Some drugs against the CXCR4 can disrupt tumor-stromal interactions and reduce tumor growth and metastatic burden. Thus, CXCR4 is regarded as a target for therapeutic intervention and noninvasive monitoring of disease progression and therapeutic guidance.

Potential roles for CXCR4 in breast cancer. Fig.1 Potential roles for CXCR4 in breast cancer. (Xu, 2015)

Biparatopic CXCR4-targeted Bispecific ADC

Many potential ADC targets present poor internalization and undergo a high rate of endocytic recycling, which leads to the ADC to return to the cell surface intact without delivering the payload to the lysosome. Bispecific biparatopic antibodies have been used for ADC development recently, which endow the ability to recognize two distinct epitopes simultaneously and offer the potential to maximize the benefits of therapeutic ADCs. Several bispecific biparatopic ADCs have emerged recently and they can promote the internalization and trafficking to the lysosome to maximize the amount of drug and effectively carry drugs to tumor cells.

Two highly selective monovalent sdAbs targeting distinct epitopes of CXCR4, 238D2, and 238D4 were linked by a short peptide linkage to form a bispecific biparatopic antibody and showed significantly increased affinity for CXCR4 and picomolar activity in antichemotactic assays. Further research results indicated that the biparatopic CXCR4 sdAb has strong antiretroviral activity against T cell-tropic and dual-tropic HIV-1 strains. Besides, the biparatopic sdAb can effectively mobilize CD34-positive stem cells in the model animals. Thus, the biparatopic CXCR4 sdAb may be used in the ADC construction for CXCR4-positive cancer therapy.

Epitope mapping of CXCR4 sdAbs. Fig.2 Epitope mapping of CXCR4 sdAbs. (Jähnichen, 2010)

What Can We Do for You?

With a highly experienced team and world-class facilities, Creative Biolabs can offer a wide variety of services for ADCs development and manufacturing. Based on mature technology, cutting-edge antibody engineering, and bioconjugation platform, as well as comprehensive successful workflows, we now provide customized solution to produce bispecific biparatopic ADCs against different markers including the CXCR4 n. Our services are customized to accelerate the development of your own ADC.

Our ADCs services include:

For more information about our services, please contact us.

References

  1. Xu, C.; et al. CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug design, development and therapy. 2015, 9: 4953.
  2. Jähnichen, S.; et al. CXCR4 sdAbs (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proceedings of the National Academy of Sciences. 2010, 107(47): 20565-20570.

For Research Use Only. NOT FOR CLINICAL USE.


Related Sections

Bispecific ADCs Development: Services:
Online Inquiry
Name:
*Phone:
*E-mail Address:
*Products or Services Interested:
Company/Institution
Project Description:









Customized FluoroAb™

Welcome! For price inquiries, please feel free to contact us through the form on the left side. We will get back to you as soon as possible.

Contact us
USA
 
 Tel:
 Fax:
 Email:
Europe
 
 Tel:
 Email:
Germany
 
 Tel:
 Email:


Inquiry

Top