ADC Development for Hodgkin Lymphoma

Antibody-drug conjugates (ADCs) are becoming an important class of cancer therapeutics and showing promising response rates when used in chemorefractory cancer patients. Thus, ADCs are developed actively to improve the outcome of cancer therapy currently. As a leader in the field of novel drug discovery service especially related to immunotherapy, Creative Biolabs is committed to the antibody discovery and bio-conjugation for more than ten years. We provide one-stop ADCs development services targeting the Hodgkin lymphoma (HL) treatment from antibody and drug production to bio-conjugation and ADCs products analysis.

Introduction of HL

HL is a B cell-derived cancer, which is one of the most frequent lymphomas. This lymphoid malignancy is associated with various organs including peripheral lymph nodes, liver, lung, and bone marrow. HL can be subclassified into nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted, and nodular lymphocyte-predominant HL (NLPHL). In classical HL, the tumor cells termed Hodgkin and Reed-Sternberg (HRS) cells are usually very rare in the tissue. These HRS cells have largely lost their B cell phenotype and show a very unfavorable co-expression of markers of various hematopoietic cell types, although they are originated from mature B cell. Thus, HRS cells present uncontrolled activation of multiple signaling pathways and transcription factors. In the majority of HL, HRS can attract many other cells by secreting chemokines and cytokines to form a heterogeneous, inflammatory-rich microenvironment. This background confers essential survival signals and helps HRS cells escape from cytotoxic T-cell or natural killer (NK)-cell-mediated attacks.

Cellular interactions in the HL microenvironment. Fig.1 Cellular interactions in the HL microenvironment. (Küppers, 2012)

ADC Development for HL

Brentuximab vedotin (SGN-35) is an ADC consisting of an anti-CD30 antibody linked to a toxic microtubule-disrupting agent monomethyl auristatin E (MMAE). It has been used in the treatment of refractory or relapsed Hodgkin lymphoma. In phase II trials, SGN-35 produced response rates of 75% in patients with HL. The efficacy of SGN-35 in Hodgkin lymphoma mainly depended on its effect on the tumor microenvironment. Diffusion of the free drug from the targeted tumor cells could achieve a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells, and elimination of cells that provide growth factor support for HRS cells could further enhance the cytotoxic activity of SGN-35. Based on the above positive effects, this ADC becomes a promising therapeutic agent and acquires accelerated approval by the FDA.

ADCT-301 is another ADC composed of human anti-CD25 IgG1 HuMax-TAC, linked to a pyrrolobenzodiazepine (PBD) dimer through a dipeptide cleavable linker. ADCT-301 can bind to human CD25 with picomolar affinity. This novel ADC has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines such as the HL. Once the ADC internalized, it releases the warhead that binding to the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links.

 A, structure of ADCT-301. B, flow cytometry measurement of median fluorescent intensity showing binding of ADCT-301, HuMax-TAC, and nonbinding ADC binding to Karpas 299 and Su-DHL-1 CD25-positive human cell lines. Fig.2 A, structure of ADCT-301. B, flow cytometry measurement of median fluorescent intensity showing binding of ADCT-301, HuMax-TAC, and nonbinding ADC binding to Karpas 299 and Su-DHL-1 CD25-positive human cell lines. (Flynn, 2016)

Target of ADC development for HL:

CD25

What Can We Do for You?

Creative Biolabs provides comprehensive ADC development services for the treatment of HL. As a well-recognized service provider in ADC preparation, we are proud to provide flexible and reliable ADC services to accelerate your research. Contact us today for a free consultation with the scientific team and discover how Creative Biolabs can be a valuable resource and partner for your organization.

References

  1. Küppers, R.; et al. Hodgkin lymphoma. The Journal of clinical investigation. 2012, 122(10): 3439-3447.
  2. Flynn, M. J.; et al. ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Molecular cancer therapeutics. 2016, 15(11): 2709-2721.


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