ADC Development for RCC

Renal cell carcinoma (RCC) is the most prevalent malignancy arising in the kidney, and the incidence is increasing every year. Traditional treatment options for this cancer show poor response. Currently, novel treatment strategy such as the antibody-drug conjugates (ADCs) is presenting promise in the treatment of RCC. Now Creative Biolabs provides the best-in-class ADC development services against RCC, and we bring together the most renowned ADC experts and long-standing experience in antibody and drug development to meet customers' requirement.

Introduction of RCC

Renal cell carcinoma (RCC) is also known as hypernephroma, renal or kidney cancer. It’s the third malignancy within urological oncology and comprises 2-3% of all malignancies. The kidneys play a critical role in body that help get rid of waste and regulate fluid balance. Tubules in kidneys can help filter the blood, excrete waste and make urine. RCC occurs upon the cancer cells growing in the tubules uncontrollably. RCC is a fast-growing cancer and often spreads to other organs such as the lungs. Several risk factors of RCC include tobacco smoking, exposure to asbestos or chemicals, dialysis treatment, hypertension, obesity, polycystic kidney disease and urinary tract infections. In the early stages of RCC, there are only few early warning signs. As the disease progresses, symptoms may include blood in the urine, fatigue, loss of appetite, weight loss, fever night sweats and excessive hair growth (in women). Currently, five kinds of standard treatments are used in the RCC, including surgery, radiation therapy, chemotherapy, biologic therapy and targeted therapy.

Stages of kidney cancer and recommended treatments. Fig.1 Stages of kidney cancer and recommended treatments. (Hsieh, 2017)

ADC Development for RCC

ADC is comprised of a monoclonal antibody conjugated to a cytotoxin, which is a new class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of cancer. ADCs represent a promising method for the treatment of RCC. For example, AGS-16M8F and AGS-16C3F are ADCs targeting RCC composed of fully human IgG2a antibodies conjugated to MMAF via a noncleavable linker. The antibody components of the two ADCs target ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3), which is expressed in a subset of renal tubules cells. Preclinical experiments indicated that both ADCs internalize and induce cytotoxicity in both in vitro and in vivo models of RCC.

Waterfall plot for AGS-16C3F (CHO): Maximum percent change from baseline in total tumor burden by best overall response and duration of treatment. Fig.2 Waterfall plot for AGS-16C3F (CHO): Maximum percent change from baseline in total tumor burden by best overall response and duration of treatment. (Thompson, 2018)

The CDX-014 is an ADC being developed to target the extracellular domain of the T cell immunoglobulin mucin domain 1 (TIM-1). It was produced with the anti-TIM-1 antibody covalently linked via a peptide linker, to a potent cytotoxin, monomethyl auristatin E (MMAE). This ADC is tested in the Phase II currently.

Vorsetuzumab mafodotin (SGN-75) is another ADC composed of an anti-CD70 humanized monoclonal antibody (vorsetuzumab), conjugated to noncleavable monomethyl auristatin F (MMAF) linker-payload. The drug completed phase I clinical trials for RCC. HKT288 is an ADC consisting of an anti-CDH6 antibody linked to DM4. Preclinical study results demonstrated that HKT288 can induce durable tumor regression of renal cancer models in vivo. It also presents an acceptable pre-clinical safety profile that facilitates the progress towards clinical evaluation.

ADC development for RCC mainly focused on the following targets:

ENPP3        TIM1        Cadherin 6        CD70

What Can We Do for You?

ADCs serve as a promising therapeutic approach for RCC treatment by combining the antigen-targeting specificity of monoclonal antibodies with the potent antitumor activity of small molecular drugs. However, to design an effective ADC, it is essential to select suitable MAb and their target, the linkers and the toxic agents. With more than ten years of experience in bio-conjugation chemistry and antibody development, Creative Biolabs offers customers comprehensive ADCs construction services against RCC from design to the production. For more detail information, please feel free to contact us.

References

  1. Hsieh, J. J.; et al. Renal cell carcinoma. Nature reviews Disease primers. 2017, 3: 17009.
  2. Thompson, J. A.; et al. Phase I Trials of Anti-ENPP3 Antibody-Drug Conjugates in Advanced Refractory Renal Cell Carcinomas. Clinical Cancer Research. 2018, 24(18): 4399-4406.

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