June 19, 2024

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Exploring CrossMab Technology and Its Diverse Applications in Medicine

Exploring CrossMab Technology and Its Diverse Applications in Medicine



Exploring CrossMab Technology and Its Diverse Applications in Medicine

CrossMab technology, developed in 2011, has emerged as a groundbreaking method for ensuring the correct pairing of antibody light chains with their respective heavy chains in bispecific antibodies.

In comparison to formats based on ScFV or Fab constructions, CrossMab has demonstrated numerous advantages in terms of production, stability, developability, and versatility.

Over the past decade, it has evolved into one of the most mature, widely used, and universally applied technologies in the field.

 

 

Structure of CrossMab:

CrossMab, built on the Knobs-into-Holes (KiH) scheme, addresses the issue of incorrect light chain pairing.

Essentially, this method designs KiH heterodimers in the Fc region and swaps the CH1 and CL regions in the Fab region to reduce light chain mismatch.

 

Exploring CrossMab Technology and Its Diverse Applications in Medicine

 

This design principle is applicable not only to heterodimer antibodies (1+1 format) targeting two antigens but also allows the creation of MonoMab (single-valent antibodies with one Fc portion) and DuoMab (bivalent antibodies with two Fc portions).

Moreover, it facilitates the correct light chain pairing in heterodimer/trimer bispecific/multispecific antibodies or fusion proteins, enabling various formats such as 2+1, 2+2, 3+1, 4+1, or 4+2, and antibody fusion proteins.

Exploring CrossMab Technology and Its Diverse Applications in Medicine

 

 

 

 

Applications in Cancer Treatment:

CrossMab technology has become a cornerstone in cancer immunotherapy research.

At least 19 bispecific antibodies and fusion proteins based on Roche’s CrossMab technology have entered clinical trials by mid-2021.

Faricimab, a leading candidate targeting Ang-2/VEGF, currently undergoing regulatory review, and glofitamab, a CD20/CD3 T-cell engaging bispecific antibody in phase 3 trials, showcase the potential of this technology in cancer treatment.

Exploring CrossMab Technology and Its Diverse Applications in Medicine

 

 

 

 

Advancements in T-Cell Engaging Antibodies:

Leading the way in T-cell engaging antibodies is glofitamab (RG6026), a 2+1 format targeting CD20 and CD3ε.

Glofitamab is being evaluated in multiple clinical trials for lymphoma patients, including those who have relapsed after CAR-T cell therapy.

Similar 2+1 T-cell engaging antibodies for the treatment of multiple myeloma and melanoma are also in phase 1 clinical trials.

 

 

Applications Beyond Oncology:

CrossMab’s impact extends beyond oncology, reaching into HIV-1 prevention and treatment.

Additionally, the technology has been leveraged to develop a bispecific antibody targeting SARS-CoV-2, displaying potential applications in infectious diseases.

 

Advancements in Autoimmune Diseases:

In autoimmune diseases, 1+1 and 2+2 CrossMab patterns targeting TNFα/IL-17 have demonstrated superior efficacy in blocking cytokine and chemokine responses.

Dual targeting of cytokines has shown better efficacy than individual cytokine inhibition, suggesting potential therapeutic options for autoimmune diseases.

 

Recent Developments in CNS Diseases:

CrossMab technology has also entered the realm of central nervous system (CNS) diseases, with BS-GANT (RG6102) showing promise in improving brain exposure and preventing plaque formation.

Currently, it is undergoing phase 2 clinical trials in patients with early-stage Alzheimer’s disease.

 

 


Conclusion:

Over the past two decades, numerous technologies have been developed to generate bispecific antibodies, and CrossMab technology stands out as a simple, direct, and clinically validated solution.

Its successful combination with the KiH technique has made it one of the most mature, versatile, and widely applied technologies in both industry and academia.

With ongoing advancements in bispecific and multispecific antibody development, CrossMab technology is poised to have a significant impact on various diseases, including cancer, infectious diseases, autoimmune conditions, CNS disorders, and metabolic diseases, bringing new hope to patients.

 

 

 

 

Exploring CrossMab Technology and Its Diverse Applications in Medicine

Reference:
“Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins.” MAbs. Jan-Dec 2021;13(1):1967714.

(source:internet, reference only)


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