We examined the role of Fc;R in antibody therapy of metastatic melanoma in wild-type and different Fc;R knockout mice. Treatment of B16F10-challenged wild-type mice with TA99 antibody specific for the gp75 tumor antigen resulted in a marked decrease in numbers of lung metastases. Treatment of individual Fc;R knock-out mice revealed the high-affinity IgG receptor, Fc;RI (CD64), to represent the central Fc;R for TA99-induced antitumor effects. The potential of immunemodulating agents to further enhance the protective effect induced by monoclonal antibody (mAb) TA99 was examined in combination treatments consisting of mAb TA99 and a TLR-4 agonist, monophosphoryl lipid A (MPL). MPL did potently boost TA99 antibody-induced effects, and combination therapy was, again, found to be dependent on the presence of

Antibody-reliant destruction of tumor cells by immune effector cells is mediated by antibody-dependent cellular cytotoxicity, in which Fc receptor (FcR) engagement is crucial. This study documents an important role for the ␤ 2 integrin Mac-1 (CD11b/CD18) in FcR-mediated protection against melanoma. CD11b-deficient mice, those that lack Mac-1, were less protected by melanoma-specific monoclonal antibody TA99 than wild-type (WT) mice. Significantly more lung metastases and higher tumor loads were observed in Mac-1 ؊/؊ mice. Histologic analyses revealed no differences in neutrophil infiltration of lung tumors between Mac-1 ؊/؊ and WT mice. Importantly, Mac-1 ؊/؊ phagocytes retained the capacity to bind tumor cells, implying that Mac-1 is essential during actual FcR-mediated cytotoxicity. In summary, this study documents Mac-1 to be required for FcR-mediated antimelanoma immunity in vivo and, furthermore, supports a role for neutrophils in melanoma rejection. IntroductionAntibody (Ab)-dependent cellular cytotoxicity (ADCC) is considered crucial for Ab-mediated tumor cell degradation. Specific Ab-Fc receptor (FcR) interactions establish close contacts between tumor targets and immune effector cells, which triggers cytotoxicity and cytokine release. Neutrophils, monocytes, macrophages, and natural killer (NK) cells can mediate ADCC via activating FcRs, which include Fc␥RIa (CD64), Fc␥RIIa (CD32), Fc␥RIIIa (CD16), and Fc␣RI (CD89) in man, and Fc␥RI and Fc␥RIII in mice. [1][2][3][4] Although Abs may affect tumor growth via FcR-unrelated mechanisms (such as complement-dependent lysis, blockade of growth factor receptors, or via induction of apoptosis), 5 in vivo antitumor effects of Abs have been documented to depend on immune activation through FcRs. [6][7][8] Numerous studies in cancer immunology focused on melanoma and melanoma-specific differentiation antigens that induce immune responses. 9 If tolerance is broken, melanosomal proteins can be recognized by T cells, which may provide B-cell help and participate in Ab production. Actual tumor rejection seems dependent on phagocytes, which may be activated by CD4 ϩ or NK cells. [10][11][12] Improved clinical outcome has, furthermore, been correlated with the presence of melanoma-specific Abs in patients. 13 Ab-mediated protection in the murine B16F10 melanoma model is well established. Monoclonal antibody (mAb) TA99, specific for melanoma differentiation antigen gp75 (brown locus protein, or TRP-1), is effective in preventing and eradicating early established metastases. 11 Studies with mice deficient in the FcR ␥ chain, lacking expression of Fc␥RI and Fc␥RIII, revealed activating FcR to be critical in TA99-mediated tumor rejection. 6 Further evidence supporting FcR dependence in Ab-mediated melanoma rejection was established by (1) the documented inability of F(abЈ) 2 fragments to mediate protection, 12 (2) lack of Ab effects on tumor cells in the absence of effector cells, 12 and (3) enhancement of antitumor immunity in Fc␥RII (inhibitory murine FcR) knock-out mice. ...

Objective Both, knee joint distraction (KJD) and high tibial osteotomy (HTO) are joint-preserving surgeries that postpone total knee arthroplasty (TKA) in younger osteoarthritis (OA) patients. Here we evaluate the 2-year follow-up of KJD versus TKA and KJD versus HTO in 2 noninferiority studies. Design Knee OA patients indicated for TKA were randomized to KJD ( n = 20; KJDTKA) or TKA ( n = 40). Medial compartmental knee OA patients considered for HTO were randomized to KJD ( n = 23; KJDHTO) or HTO ( n = 46). Patient-reported outcome measures were assessed over 2 years of follow-up. The radiographic joint space width (JSW) was measured yearly. In the KJD groups, serum-PIIANP and urinary-CTXII levels were measured as collagen type-II synthesis and breakdown markers. It was hypothesized that there was no clinically important difference in the primary outcome, the total WOMAC, when comparing KJD with HTO and with TKA. Results Both trials were completed, with 114 patients (19 KJDTKA; 34 TKA; 20 KJDHTO; 41 HTO) available for 2-year analyses. At 2 years, the total WOMAC score (KJDTKA: +38.9 [95%CI 28.8-48.9] points; TKA: +42.1 [34.5-49.7]; KJDHTO: +26.8 [17.1-36.6]; HTO: +34.4 [28.0-40.7]; all: P < 0.05) and radiographic minimum JSW (KJDTKA: +0.9 [0.2-1.6] mm; KJDHTO: +0.9 [0.5-1.4]; HTO: +0.6 [0.3-0.9]; all: P < 0.05) were still increased for all groups. The net collagen type-II synthesis 2 years after KJD was increased ( P < 0.05). Half of KJD patients experienced pin tract infections, successfully treated with oral antibiotics. Conclusions Sustained improvement of clinical benefit and (hyaline) cartilage thickness increase after KJD is demonstrated. KJD was clinically noninferior to HTO and TKA in the primary outcome.

KJD shows long-lasting clinical and structural improvement. In addition to a greater survival rate for males (>two out of three), the initial cartilage repair activity appears to be important for long-term clinical success.